Antiarrhythmic benzodiazepines

ABSTRACT

Benzo-(1,5)-diazepine derivatives with an amide or urea function in the 3-position are useful in the treatment of arrhythmia. The compounds have structural formulae: ##STR1##

SUMMARY OF THE INVENTION

This invention is concerned with a novel method of treating arrhythmiaby the administration of a compound of general structural formula:##STR2##

The invention is also concerned with pharmaceutical formulationscomprising one or more of the novel compounds as active ingredient,either alone or in combination with one or more of a Class I, Class IIor Class IV antiarrhythmic agent.

BACKGROUND OF THE INVENTION

Arrhythmias often occur as complications to cardiac diseases such asmyocardial infarction and heart failure. In a serious case, arrhythmiasgive rise to a ventricular fibrillation and can cause sudden death.

Though various antiarrythmic agents are now available on the market,those, having both satisfactory effects and high safety, have not beenobtained. For example, antiarrythmic agents of Class I according to theclassification of Vaughan-Williams which cause a selective inhibition ofthe maximum velocity of the upstroke of the action potential (Vmax) areinadequate for preventing ventricular fibrillation. In addition, theyhave problems regarding safety, namely, they cause a depression of themyocardial contractility and have a tendency to induce arrythmias due toan inhibition of the impulse conduction. Beta-adrenoceptor blockers andcalcium antagonists which belong to Class II and IV respectively, have adefect that their effects are either limited to a certain type ofarrhythmia or are contraindicated because of their cardiac depressantproperties in certain patients with cardiovascular disease. Theirsafety, however, is higher than that of the antiarrhythmic agents ofClass I.

Antiarrythmic agents of Class III are drugs which cause a selectiveprolongation of the duration of the action potential without asignificant depression of the Vmax. Drugs in this class are limited.Examples such as Sotalol and amiodarone have been shown to possess ClassIII properties. Sotalol also possesses Class II effects which may causecardiac depression and be contraindicated in certain susceptiblepatients. Also, amiodarone is severely limited by side effects. Drugs ofthis class are expected to be effective in preventing ventricularfibrillations. Pure Class III agents, by definition, are not consideredto cause myocardial depression or an induction of arrhythmias due to theinhibition of the action potential conduction as seen with Class Iantiarrhythmic agents.

DETAILED DESCRIPTION OF THE INVENTION

The compounds useful in the novel method of treatment of this inventionhave structural formula: ##STR3## or a pharmaceutically acceptable saltthereof, wherein A is

1) thieno,

2) pyrido, or

3) benzo either unsubstituted or substituted with --NH₂ --NHSO₂ (C₁₋₃alkyl), C₁₋₃ alkyl or C₁₋₃ alkoxy;

X is

1) ═O,

2) ═S,

3) ═N--NH₂,

4) ═N--OH or

5) ═H₂ ;

Y is

1) ═O,

2) ═N--CN or

3) ═H₂ ;

Z is

1) C₁₋₆ alkylene, either straight or branch chain and eitherunsubstituted or substituted with phenyl or spiropiperidine,

2) C₂₋₄ alkenylene, either straight or branch chain,

3) --(CH₂)_(m) --W--(CH₂)_(n) -- wherein m and n are independently 0, 1,2, 3 or 4 and W is --O--, --S-- or --NH,

4) 4-(5-methylisoxazole-3-yl),

5) C₃₋₆ cycloalkylene, or

6) single bond;

p is 0 or 1;

R¹ is

1) phenyl, either unsubstituted or substituted with one or twosubstituents selected from

a) --NO₂,

b) --Cl, Br, F, or I,

c) --CF₃,

d) --C₁₋₃ alkyl,

e) --C₁₋₃ alkoxy,

f) --CN,

g) -methylenedioxy,

2) C₅₋₇ cycloalkyl,

3) ##STR4## 4) mono- or bicyclic heterocyclyl of 5 to 10 members one ortwo of which are sulfur, nitrogen or oxygen, the remaining being carbon,such as 2-thienyl, 2-furanyl, 2-indolyl, 2-quinoxolinyl, or2-(2,3-dihydro benzofuranyl)

5) C₁₋₃ alkyl, or

6) indan-5-yl;

R² is

1) phenyl, either unsubstituted or substituted with C₁₋₃ alkoxy or4,4-dimethyloxazolin-2-yl,

2) C₁₋₆ alkyl, either straight or branched chain, and eitherunsubstituted or substituted with C₁₋₃ alkoxy or C₁₋₃ alkoxy-C₁₋₃alkoxy,

3) C₅₋₇ cycloalkyl,

4) 2- or 3-furyl,

5) 1-methylpiperidin-2-yl, or

6) if R² is phenyl, the 2-position of the phenyl can be joined to the4-position nitrogen of the diazepine ring through a carbonyl group andthe double bond between the 4-nitrogen and the 5-carbon becomes a singlebond;

R³ is

1) hydrogen or

2) C₁₋₃ alkyl either unsubstituted or substituted with --N(CH₃)₂, --OH,--CF₃, or

3) --CF₃ ;

R⁴ is

1) hydrogen,

2) C₁₋₆ alkyl, the chain of carbon atoms of which can be interrupted byone or two non-adjacent oxygen atoms and which is either unsubstitutedor substituted with C₁₋₃ alkoxycarbonyl, --OH or ##STR5## 3)tetrazol-5-yl; R⁵ is hydrogen or oxygen or is joined to R² to form thepartial structure: ##STR6## the bond represented by is: 1) a double bondwhen p is zero or when p is 1 and R⁵ is oxygen, or

2) a single bond when R⁵ is hydrogen or R⁵ is joined to R² to form thepartial structure: ##STR7##

This invention is meant to include the individual diastereomers wheresuch exist and mixtures thereof and enantiomers and mixtures of theenantiomers.

The pharmaceutically acceptable salts of the compounds of Formulas Iinclude the conventional non-toxic salts or the quarternary ammoniumsalts of the compounds of Formula I formed, e.g., from non-toxicinorganic or organic acids. For example, such conventional non-toxicsalts include those derived from inorganic acids such as hydrochloric,hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; andthe salts prepared from organic acids such as acetic, propionic,succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic,pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic,salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic,methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.

The pharmaceutically acceptable salts of the present invention can besynthesized from the compounds of Formula I which contain a basic oracidic moiety by conventional chemical methods. Generally, the salts areprepared by reacting the free base or acid with stoichiometric amountsor with an excess of the desired salt-forming inorganic or organic acidor base in a suitable solvent or various combinations of solvents.

One embodiment of this invention are novel compounds useful in the novelmethod of treatment of this invention wherein:

A is benzo;

X and Y are oxygen;

R³ is methyl;

R⁴ is hydrogen; and

R² is C₁₋₆ alkyl.

Specific novel compounds representative of this embodiment are those ofthe following structure and specified in Table I:

                  TABLE I                                                         ______________________________________                                         ##STR8##                                                                            R.sup.1       R.sup.2                                                  ______________________________________                                               2,4-diClPh    CH.sub.3                                                        2,4-diClPh    C.sub.2 H.sub.5                                                 2,4-diClPh                                                                    t-Bu                                                                          4-CF.sub.3 Ph i-C.sub.3 H.sub.7                                               cyclohexyl    i-C.sub.3 H.sub.7                                               2,4-diClPh    i-C.sub.3 H.sub.7                                        ______________________________________                                    

Another embodiment of the compounds useful in the novel method oftreatment of this invention is that wherein:

A is ##STR9## X and Y are oxygen; R³ is methyl;

R⁴ is hydrogen; and

R² is phenyl.

A class of novel compounds within this embodiment is that withstructural formula: ##STR10## wherein Z is C₁₋₆ alkylene or a bond andR¹ is phenyl, phenyl substituted with --Cl, --Br, --I, --F, or --CF₃, orR¹ is cyclohexyl.

Specific novel compounds representative of this class are those depictedin the following Table II:

                  TABLE II                                                        ______________________________________                                        Z                    R.sup.1                                                  ______________________________________                                        --(CH.sub.2).sub.2 --                                                                              2,4-diClPh                                               --(CH.sub.2).sub.2 --                                                                              4-ClPh                                                   --(CH.sub.2).sub.2 --                                                                              2,4-diFPh                                                --(CH.sub.2).sub.2 --                                                                              2-ClPh                                                   --(CH.sub.2).sub.2 --                                                                              4-CF.sub.3 Ph                                            --CH.sub.2 --        4-CF.sub.3 Ph                                            --(CH.sub.2).sub.2 --                                                                              3-CF.sub.3 Ph                                            --(CH.sub.2).sub.2 --                                                                              2-CF.sub.3 Ph                                            --(CH.sub.2).sub.2 --                                                                              cyclohexyl                                                 --                 cyclohexyl                                               --(CH.sub.2).sub.3-- cyclohexyl                                               --CH.sub.2 --        cyclohexyl                                               --(CH.sub.2).sub.2 --                                                                              Ph                                                       --CH.sub.2 --        Ph                                                       --(CH.sub.2).sub.2 --                                                                              4-CNPh                                                   --(CH.sub.2).sub.2 --                                                                              3-ClPh                                                   --(CH.sub.2).sub.3 --                                                                              Ph                                                       --(CH.sub.2).sub.2 --                                                                              3-CNPh                                                   --(CH.sub.2).sub.3   2-thienyl                                                ______________________________________                                    

Another class of novel compounds within this embodiment is that withstructural formula: ##STR11## wherein Z is C₂₋₄ alkenylene and R¹ isphenyl or phenyl substituted with --Cl, --Br, --F, --I, --CF₃, C₁₋₃alkyl, C₁₋₃ alkoxy or methylenedioxy.

Specific novel compounds representative of this class are those depictedin the following Table III:

                  TABLE III                                                       ______________________________________                                        Z                 R.sup.1                                                     ______________________________________                                        CHCH              4-NO.sub.2 Ph                                               CHCH              2,4-diClPh                                                  CHCH              3-ClPh                                                      CHCH              2-ClPh                                                      CHCH              2,4-diFPh                                                   CHCH              2,6-diClPh                                                  CHCH              4-CF.sub.3 Ph                                               CHCH              2-BrPh                                                      CHCH              4-lPh                                                       CHCH              4-BrPh                                                       ##STR12##        Ph                                                          CHCH              Ph*                                                         CHCH              3,4-diClPh                                                  CHCH              4-CH.sub.3 Ph                                               CHCH              4-CH.sub.3 OPh                                              CHCH              3,4-methylenedioxyPh                                        CHCH              3-BrPh                                                      ______________________________________                                         *This compound is known in U.S. Pat. No. 4,820,834                       

A third embodiment of the compounds useful in the novel method oftreatment of this invention is that wherein: Z is --NH--.

Compounds representative of this embodiment are those disclosed in thefollowing Table IV.

                                      TABLE IV                                    __________________________________________________________________________     ##STR13##                                                                    A      R.sup.1   R.sup.2                                                                              R.sup.3  Y                                            __________________________________________________________________________    benzo  3-CH.sub.3 Ph                                                                           Ph                                                                                    ##STR14##                                                                             O                                            benzo  2,4-diClPh                                                                              Ph     CH.sub.3 O                                            benzo  3-CH.sub.3 Ph                                                                            ##STR15##                                                                           n-C.sub.3 H.sub.7                                                                      O                                            benzo  CH.sub.2 Cyclohexyl                                                                     Ph     CH.sub.3 NCN                                          benzo  3-CH.sub.3 Ph                                                                           Ph     CH.sub.3 O                                            benzo  5-indanyl Ph                                                                                    ##STR16##                                                                             O                                             ##STR17##                                                                           3-CH.sub.3 Ph                                                                           Ph     CH.sub.3 O                                            __________________________________________________________________________

Other specific compounds included within the broadest genus but notincluded in one of the embodiments previously described are as shown inTable V.

    TABLE V      ##STR18##       A Z R.sup.1 R.sup.2 R.sup.3 R.sup.4 X Y      ##STR19##      (CH.sub.2) 2,4-diClPh Ph CH.sub.3 H O O      ##STR20##      (CH.sub.2).sub.2  2,4-diClPh Ph CH.sub.3 H O O      ##STR21##      (CH.sub.2).sub.2  2,4-diClPh Ph CH.sub.3 H O O      ##STR22##      (CH.sub.2).sub.2  cyclohexyl Ph CH.sub.3 H O O  benzo CH.sub.2 O     4-NO.sub.2      Ph Ph CH.sub.3     ##STR23##      O H.sub.2  benzo CH.sub.2 O 4-NO.sub.2 Ph Ph CH.sub.3 H O H.sub.2 benzo (     CH.sub.2).sub.2  2-CH.sub.3 OPh Ph CH.sub.3 CH.sub.3 O H.sub.2 benzo     CHCH 4-ClPh Ph CH.sub.3 H O H.sub.2 benzo (CH.sub.2).sub.2  4-ClPh Ph     CH.sub.3 H O H.sub.2      benzo     ##STR24##      4-ClPh Ph CH.sub.3 H O O      benzo --     ##STR25##      Ph CH.sub.3 H O O      benzo     ##STR26##      Ph Ph CH.sub.3 H O O      benzo     ##STR27##      2.ClPh Ph CH.sub.3 H O O      benzo --     ##STR28##      Ph CH.sub.3 H O O      benzo     ##STR29##      Ph Ph CH.sub.3 H O O  benzo -- Ph Ph CH.sub.3 H O O      benzo     ##STR30##      Ph Ph CH.sub.3 H O O      benzo     ##STR31##      Ph Ph CH.sub.3 H O O      benzo     ##STR32##      2,4-diClPh Ph CH.sub.3 H O O      benzo     ##STR33##      Ph Ph CH.sub.3 H O O      benzo     ##STR34##      Ph Ph CH.sub.3 H O O      benzo     ##STR35##      Ph Ph CH.sub.3 H S O  benzo (CH.sub.2).sub.4 CH.sub.3 Ph CH.sub.3      ##STR36##      O O  benzo (CH.sub.2).sub.4  CH.sub.3 Ph CH.sub.3 (CH.sub.2).sub.5 OH O     O benzo (CH.sub.2).sub.3       CH.sub.3 Ph CH.sub.3 H O O benzo (CH.sub.2).sub.4  CH.sub.3 Ph     CH.sub.3 H O O benzo (CH.sub.2).sub.5  CH.sub.3 Ph CH.sub.3 H O O benzo     (CH.sub.2).sub.2       CH(CH.sub.3).sub.2 Ph CH.sub.3 H O O benzo (CH.sub.2).sub.2       cyclohexyl Ph CH.sub.3 (tetrazol-1-yl)- O O      methyl  benzo     (CH.sub.2).sub.2       cyclohexyl Ph H H     ##STR37##      O  benzo (CH.sub.2).sub.2       2,4-diClPh     ##STR38##      CH.sub.3 H O O  benzo (CH.sub.2).sub.4 S CH.sub.3 Ph CH.sub.3 H O O     benzo (CH.sub.2).sub.2       cyclohexyl Ph CH.sub.3 H S O benzo (CH.sub.2)-.sub.2 cyclohexyl Ph     CH.sub.3 H H.sub.2 O      benzo     ##STR39##      Ph Ph CH.sub.3 H O O      benzo --     ##STR40##      Ph CH.sub.3 H O O  benzo (CH.sub.2).sub.2      ##STR41##      Ph CH.sub.3 H O O  benzo (CH.sub.2).sub.2       2,4-diClPh     ##STR42##      CH.sub.3 H O O  benzo (CH.sub.2).sub.2       cyclohexyl     ##STR43##      CH.sub.3 H O O  benzo (CH.sub.2).sub.2  4-CF.sub.3      Ph     ##STR44##      CH.sub.3 H O O  benzo (CH.sub.2).sub.2       2,4-diClPh     ##STR45##      CH.sub. 3 H O O      benzo     ##STR46##      Ph cyclohexyl CH.sub.3 H O O      benzo     ##STR47##      Ph Ph CH.sub.3 H O O      benzo     ##STR48##      2,4-diClPh Ph CH.sub.3 H O O      benzo --     ##STR49##      Ph CH.sub.3 H O O      benzo     ##STR50##      4-CF.sub.3 Ph Ph CH.sub.3 H O O      benzo     ##STR51##      Ph Ph CH.sub.3 H O O      benzo     ##STR52##      Ph Ph CH.sub.3 H O O      benzo     ##STR53##      2,4-diClPh Ph      ##STR54##      H O O      benzo     ##STR55##      cyclohexyl Ph H H S O      benzo     ##STR56##      cyclohexyl Ph CH.sub.3      ##STR57##      O O  benzo (CH.sub.2).sub.4       CH.sub.3 Ph CH.sub.3     ##STR58##      O O      ##STR59##      (CH.sub.2).sub.2  2,4-diClPh Ph CH.sub.3 H O O      ##STR60##      (CH.sub.2).sub.2  cyclohexyl Ph CH.sub.3 H O O  benzo (CH.sub.2).sub.2     cyclohexyl Ph H H NNH.sub.2 O benzo (CH.sub.2).sub.2  cyclohexyl Ph     CH.sub.3 (tetrazol-2-yl)- O O      methyl  benzo (CH.sub.2).sub.2     4-CF.sub.3      Ph     ##STR61##      CH.sub.3 H O O  benzo (CH.sub.2).sub.2  cyclohexyl cyclohexyl CH.sub.3     H O O      ##STR62##      (CH.sub.2).sub.2  4-CF.sub.3 Ph Ph CH.sub.3 H O O      benzo (CH.sub.2).sub. 2  cyclohexyl 3-furyl CH.sub.3 H O O benzo     (CH.sub.2).sub.2  cyclohexyl Ph CH.sub.3 CH.sub.2 CO.sub.2 Et O O benzo     (CH.sub.2).sub.4  CH.sub.3 Ph CH.sub.3 CH.sub.2 CO.sub.2 Et O O benzo     (CH.sub.2).sub.4  CH.sub.3 Ph CH.sub.3 CH.sub.2      OH O O

Representative of compounds wherein p is 1 is the compound of structuralformula: ##STR63##

Representative of compounds wherein the bond between the 4 and 5positions is a single bond is the compound of structural formula:##STR64##

Representative of compounds wherein the bond represents a single bondand R⁵ is joined to R² is the compound of structural formula: ##STR65##

Another embodiment of this invention is a group of compounds, active inthe novel method of treatment of this invention, which are novelcompounds per se. These novel compounds are depicted in the followingTable VI. ##STR66##

                                      TABLE VI                                    __________________________________________________________________________     Ex. No.                                                                                   R.sup.4          X     Y                                                                               ZR.sup.1                                __________________________________________________________________________    44  benzo   H                O     O                                                                                ##STR67##                               55  benzo   H                O     O                                                                                ##STR68##                                3  benzo   H                O     O                                                                                ##STR69##                               56  benzo   H                O     O                                                                                ##STR70##                               38  benzo   H                O     O                                                                                ##STR71##                                6  benzo   H                O     O                                                                                ##STR72##                               49  benzo   H                O     O                                                                                ##STR73##                               22  benzo   H                O     O                                                                                ##STR74##                               80                                                                                 ##STR75##                                                                            H                O     O                                                                                ##STR76##                               77                                                                                 ##STR77##                                                                            H                O     O                                                                                ##STR78##                               78                                                                                 ##STR79##                                                                            H                O     O                                                                                ##STR80##                               62  benzo                                                                                  ##STR81##       O     H.sub.2                                                                          ##STR82##                               63  benzo   H                O     H.sub.2                                                                          ##STR83##                               64  benzo   H                O     H.sub.2                                                                          ##STR84##                               70  benzo   H                                                                                               ##STR85##                                                                          O                                                                                ##STR86##                               70  benzo   H                                                                                               ##STR87##                                                                          O                                                                                ##STR88##                               __________________________________________________________________________

The compounds useful in the novel method of treatment of the presentinvention, have the pharmacological properties required for theantiarrhythmic agents of Class III, namely the prolongation of themyocardial action potential in vitro, without a significant depressionof the Vmax, and the prolongation of QTc-internal in anesthetized dogs.

These compounds are effective in treating and preventing all types ofarrhythmias including ventricular and atrial (supraventricular)arrhythmias. The compounds of the present invention are especiallyuseful to control reentrant arrhythmias and prevent sudden death due tothe ventricular fibrillation. These compounds are also effective intreating and preventing impaired cardiac pump functions.

In the novel method of this invention of treating arrhythmia, one of thecompounds or pharmaceutically acceptable salt thereof, is administeredin an amount ranging from about 0.0001 to about 20 mg per kg or bodyweight per day, preferably from about 0.001 to about 10 mg per kg ofbody weight per day in a single dose or in 2 to 4 divided doses.

These compounds can be administered as the sole active ingredient or incombination with other antiarrhythmic agents or other cardiovascularagents.

These compounds, or pharmaceutically acceptable salts thereof, in thedescribed dosages, are administered orally, intraperitoneally,subcutaneously, intramuscularly, transdermally, as sublingually orintravenously. They are preferably administered intravenously or orally,for example in the form of tablets, troches, capsules, elixirs,suspensions, syrups, wafers, chewing gum, or the like prepared by artrecognized procedures. The amount of active compound in suchtherapeutically useful compositions or preparations is such that asuitable dosage will be obtained.

The activity of the compounds described herein as antiarrhythmic agentsis measured by their ability to block the IKs and IKr as determined bythe following test protocol.

Outward potassium currents are measured in single guinea pig ventricularmyocytes using a whole-cell voltage clamp technique described in detailelsewhere (Sanguinetti and Jurkiewicz, 1990. Two components of cardiacdelayed actifier K⁺ current: differential sensitivity to block by ClassIII antiarrhythmic agents. J. Gen Physiol. 96: 195-215). Myocytes areisolated by enzymatic (collagenase and protease) digestion of Langandorfperfused hearts. Single cells are then voltage clamped using 1 mmsquare-bore pipettes filled with 0.5M Kgluconate, 25 mM KCl, 5 mMK(2)ATP. Cells are bathed in a solution containing, in mN: 132 NaCl,4KCl, 1.2 MgCl[2], 10 HEPES, 10, glucose: pH 7.2, temp. 35° C.

Each cell is maintained at a holding potential of -50 mV. Testdepolarizations are applied as voltage ramps from --85 to -50 mV, and assteps to -10 mV (0.5 s) and +50 mV (1.0 s). I[KI] is measured as peakoutward current during the voltage ramp. I[Kr] is measured as tailcurrents upon repolarization from -10 mV to -50 mV. I[KS] is measured astime-dependent current during the pulse to +50 mV. Currents are measuredduring control, then after exposure to drug at two differentconcentrations.

Employing this test the compounds described herein have an IC₅₀ of lessthan 1000 nM as IKs and/or IKr blockers.

The compounds useful in the novel method of treatment of this inventionare either known in the art or are structurally similar to compoundsknown in the art and known to have CCK-B antagonist activity. See forexample U.S. Pat. Nos. 4,820,834 and 5,004,741 by Evans et al. Processesfor the preparation of the named compounds are therefore obvious to oneskilled in the art. Typical synthetic schemes employed in making thecompounds herein are illustrated below. ##STR89##

EXAMPLE 1 ##STR90##(E)-(+)-N-[(3R)-2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-3-phenyl-2-propenamide

A solution of (E)-3-phenyl-2-propenoyl chloride (367 mg, 2.2 mmol) inmethylene chloride (1 mL) was added to a solution of3(R)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one (J.Org. Chem. 1987, 52, 3232-3239) (531 mg, 2.0 mmol) and triethylamine(307 μL, 225 mg, 2.2 mmol) in methylene chloride (10 mL). The mixturewas stirred at room temperature for 25 min. and the solvent wasevaporated under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel, eluting with CH₂ Cl₂ /Et₂ O (95:5)and the residue was triturated with Et₂ O. The solid was collected anddried in vacuo at 70° C. to give(E)-(+)-N-[(3R)-2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-3-phenyl-2-propenamideas a colorless solid (170 mg, 21%), m.p. 140°-142° C., [α] _(D) +86.7°(c=0.173, CH₂ Cl₂).

δ_(H) (CDCl₃) 7.70-7.26 (16H, m), 6.63 (1H, d, J 15.6 Hz), 5.68 (1H, d,J 8.3 Hz), and 3.50 (3H, s). Anal. Calcd. for C₂₅ H₂₁ N₃ O₂.0.15 (C₂H₅)₂ O: C, 75.63; H, 5.58; N, 10.33. Found: C, 75.29; H, 5.57; N,10.33%.

Employing the procedure substantially as described above, butsubstituting an appropriate acid chloride for the(E)-3-phenyl-2-propenoyl chloride, the following compounds wereprepared:

EXAMPLE 2 ##STR91##(+)-N-[(3R)-2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]benzamide

m.p. 224°-225° C., [α]_(D) +89.2° (c=0.141, CH₂ Cl₂). δ_(H) (CDCl₃) 8.04(1H, d, J 8.1 Hz), 7.96 (2H, d, J 6.8 Hz), 7.64-7.36 (10H, m), 7.27 (2H,t, J 7.6 Hz), 5.74 (1H, d, J 7.8 Hz), and 3.51 (3H, s). Anal. Calcd. forC₂₃ H₁₉ N₃ O₂.0.20H₂ O: C, 74.06; H, 5.24; N, 11.26. Found: C, 74.13; H,5.12; N, 11.16%.

EXAMPLE 3 ##STR92## First diastereoisomer to elute:(-)-N-[(3R)-2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl](trans-2-phenyl-1-cyclopropane)carboxamide

m.p. 180°-181° C., [α]_(D) -155.8° (c=0.434, CH₂ Cl₂). δ_(H) (CDCl₃)7.62-7.09 (15H, m), 5.59 (1H, d, J 8.1 Hz), 3.47 (3H, s), 2.52-2.45 (1H,m), 1.90-1.84 (1H, m), 1.69-1.56 (1H, m), and 1.38-1.32 (1H, m). Anal.Calcd. for C₂₆ H₂₃ N₃ O₂.0.25H₂ O: C, 75.43; H, 5.72; N, 10.15. Found:C, 75.38; H, 5.64; N, 9.94%.

Second diastereoisomer to elute:

(+)-N-[(3R)-2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl](trans-2-phenyl-1-cyclopropane)carboxamide

m.p. 104°-107° C., [α]_(D) +328.2° (c=0.098, CH₂ Cl₂). δ_(H) (CDCl₃)7.62-7.13 (15H, m), 5.60 (1H, d, J 8.3 Hz), 3.48 (3H, s), 2.59-2.54 (1H,m), 1.93-1.87 (1H, m), 1.62-1.56 (1H, m, overlaps with water), and1.33-1.25 (1H, m). Anal. Calcd. for C₂₆ H₂₃ N₃ O₂.0.50H₂ O.0.45PhCH₃ :C, 76.13; H, 5.95; N, 9.14. Found: C, 76.10; H, 5.94; N, 9.17%.

EXAMPLE 4 ##STR93##(+)-N-[(3R)-2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-1H-indole-2-carboxamide

m.p. 167°-177° C., [α]_(D) +113° (c=1.103, CH₂ Cl₂). δ_(H) (CDCl₃) 9.15(1H, br s), 8.10 (1H, d, J 9.0 Hz), 7.75-7.10 (14H, m), 5.75 (1H, d, J9.0 Hz), and 3.50 (3H, s). Anal. Calcd. for C₂₅ H₂₀ N₄ O₂ : C, 73.51; H,4.94; N, 13.72. Found: C, 73.31; H, 4.80; N, 13.62%.

EXAMPLE 5 ##STR94##(+)-N-[(3R)-2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]heptanamide

m.p. 49°-54° C., [α]_(D) +69.5° (c=1.000, MeOH). Anal. Calcd. for C₂₃H₂₇ N₃ O₂.0.40H₂ O: C, 71.81; H, 7.28; N, 10.92. Found: C, 71.90; H,7.09; N, 10.85%.

EXAMPLE 6 ##STR95##(+)-N-[(3R)-2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]hexanamide

[α]_(D) +72.6° (c=0.920, MeOH). Anal. Calcd. for C₂₂ H₂₅ N₃ O₂ : C,72.70; H, 6.93; N, 11.56. Found: C, 72.44; H, 6.75; N, 11.25%.

EXAMPLE 7 ##STR96##(+)-N-[(3R)-2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]pentanamide

[α]_(D) +68.2° (c=1.310, MeOH). Anal. Calcd. for C₂₁ H₂₃ N₃ O₂.0.25CHCl₃: C, 68.21; H, 6.26; N, 11.26. Found: C, 68.2; H, 6.29; N, 11.17%.

EXAMPLE 8 ##STR97##(+)-N-[(3R)-2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-3-phenylpropanamide

Oxalyl chloride (158 μL, 230 mg, 1.81 mmol) was added to a mixture of3-phenylpropanoic acid (249 mg, 1.66 mmol) and DMF (1 drop) in THF (10mL) and the mixture was stirred at room temperature for 40 min.3(R)-Amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one (J.Org. Chem. 1987, 52, 3232-3239) (400 mg, 1.51 mmol) and triethylamine(252 μL, 183 mg, 1.81 mmol) were added and the mixture was stirred atroom temperature for 18 h. The mixture was poured into saturated aqueoussodium hydrogen carbonate (20 mL) and extracted with ethyl acetate (3×20mL). The combined organic fractions were dried (Na₂ SO₄) and the solventwas evaporated under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel, eluting with CH₂ Cl₂ /Et₂ O (95:5)and the residue was recrystallized from toluene/hexane to give(+)-N-[(3R)-2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-3-phenylpropanamideas a colorless solid (380 mg, 63%), m.p. 179° C., [α]_(D) +100.4°(c=0.225, CH₂ Cl₂).

δ_(H) (CDCl₃) 7.62-7.57 (2H, m), 7.47-7.21 (13H, m), 5.54 (1H, d, J 8.1Hz), 3.47 (3H, s), 3.03 (2H, t, J 7.8 Hz), and 2.73-2.67 (2H, m). Anal.Calcd. for C₂₅ H₂₃ N₃ O₂.0.15H₂ O: C, 75.04; H, 5.87; N, 10.50. Found:C, 75.06; H, 5.78; N, 10.55%.

Employing the procedure substantially as described above, butsubstituting an appropriate carboxylic acid for the 3-phenylpropanoicacid, the following compounds were prepared:

EXAMPLE 9 ##STR98##E-(+)-N-[(3R)-2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-3-(3,4-dichlorophenyl)-2-propenamide

m.p. 145°-147° C., [α]_(D) +77.8° (c=0.126, CH₂ Cl₂). δ_(H) (CDCl₃)7.64-7.25 (14H, m), 6.61 (1H, d, J 15.6 Hz), 5.65 (1H, d, J 8.0 Hz), and3.50 (3H, s). Anal. Calcd. for C₂₅ H₁₉ N₃ O₂ Cl₂ : C, 64.67; H, 4.12; N,9.05. Found: C, 64.57; H, 4.25; N, 9.01%.

EXAMPLE 10 ##STR99##E-(+)-N-[(3R)-2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]3-(4-nitrophenyl)-2-propenamide

m.p. 165°-166° C., [α]_(D) +80.5 (c=0.126, CH₂ Cl₂). δ_(H) (CDCl₃) 8.26(1H, d, J 8.8 Hz), 7.74-7.28 (13H, m), 6.76 (1H, d, J 15.6 Hz), 5.66(1H, d, J 8.0 Hz), and 3.51 (3H, s). Anal. Calcd. for C₂₅ H₁₉ N₄ O₄ : C,68.17; H, 4.58; N, 12.72. Found: C, 68.25; H, 4.65; N, 12.57%.

EXAMPLE 11 ##STR100##E-(+)-N-[(3R)-2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-3-(2,4-dichlorophenyl)-2-propenamide

m.p. 137°-139° C., [α]_(D) +66.0° (c=0.144, CH₂ Cl₂). δ_(H) (CDCl₃) 8.02(1H, d, J 15.6 Hz), 7.73-7.26 (13H, m), 6.66 (1H, d, J 15.6 Hz), 5.81(1H, d, J 8.8 Hz), and 3.53 (3H, s). Anal. Calcd. for C₂₅ H₁₉ Cl₂ N₃ O₂: C, 64.67; H, 4.12; N, 9.05. Found: C, 64.28; H, 4.24; N, 8.83%.

EXAMPLE 12 ##STR101##E-(+)-N-[(3R)-2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-3-(4-methylphenyl)-2-propenamide

m.p. 133°-135° C., [α]_(D) +90.4° (c=0.125, CH₂ Cl₂). δ_(H) (CDCl₃)7.68-7.19 (15H, m), 6.59 (1H, d, J 15.6 Hz), 5.70 (1H, d, J 8.0 Hz),3.50 (3H, s), and 2.38 (3H, s). Anal. Calcd. for C₂₆ H₂₃ N₃ O₂ : C,76.26; H, 5.66; N, 10.26. Found: C, 75.93; H, 5.82; N, 10.10%.

EXAMPLE 13 ##STR102##E-(+)-N-[(3R)-2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-3-(4-methoxyphenyl)-2-propenamide

m.p. 129°-133° C., [α]_(D) +89.9° (c 0.188, CH₂ Cl₂). δ_(H) (CDCl₃)7.65-7.24 (14H, m), 6.92 (1H, d, J 8.8 Hz), 6.50 (1H, d, J 15.6 Hz),5.69 (1H, d, J 8.0 Hz), 3.84 (3H, s), and 3.50 (3H, s). Anal. Calcd. forC₂₆ H₂₃ N₃ O₃.0.30H₂ O: C, 72.48; H, 5.52; N, 9.75. Found: C, 72.75; H,5.60; N, 9.36%.

EXAMPLE 14 ##STR103##(+)-N-[(3R)-2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-3-(2,4-dichlorophenyl)propanamide

m.p. 92°-95° C., [α]D90.5° (c=0.196, CH₂ Cl₂). δ_(H) (CDCl₃) 7.62-7.15(13H, m), 5.52 (1H, d, J 8.1 Hz), 3.47 (3H, s), 3.10 (2H, t, J 7.6 Hz),and 2.68 (2H, dd, J 7.6, 2.8 Hz). Anal. Calcd. for C₂₅ H₂₁ Cl₂ N₃O₂.0.20H₂ O: C, 63.89; H, 4.59; N, 8.94. Found: C, 63.86; H, 4.62; N,8.87%.

EXAMPLE 15 ##STR104##E-(+)-N-[(3R)-2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-3-(3-chlorophenyl)-2-propenamide

m.p. 229°-231° C., [α]_(D) +86.2° (c=0.225, CH₂ Cl₂). δ_(H) (CDCl₃)7.64-7.26 (15H, m), 6.62 (1H, d, J 15.6 Hz), 5.66 (1H, d, J 8.1 Hz), and3.50 (3H, s). Anal. Calcd. for C₂₅ H₂₀ ClN₃ O₂ : C, 69.85; H, 4.69; N.9.77. Found: C, 70.20; H, 4.83; N, 9.41%.

EXAMPLE 16 ##STR105##E-(+)-N-[(3R)-2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-3-(2-chlorophenyl)-2-propenamide

m.p. 128°-131° C., [α]_(D) =+61.7° (c=0.196, CH₂ Cl₂). δ_(H) (CDCl₃)8.06 (1H, d, J 15.6 Hz), 7.65-7.28 (14H, m), 6.62, (1H, d, J 15.6 Hz),5.68 (1H, d, J 8.3 Hz), and 3.50 (3H, s). Anal. Calcd. for C₂₅ H₂₀ ClN₃O₂.0.20H₂ O: C, 69.27; H, 4.74; N, 9.69. Found: C, 69.21; H, 4.68; N,9.45%.

EXAMPLE 17 ##STR106##E-(+)-N-[(3R)-2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-3-(2,4-difluorophenyl)-2-propenamide

m.p. 121°-123° C., [α]_(D) +76.8° (c=0.111, CH₂ Cl₂). δ_(H) (CDCl₃) 7.71(1H, d, J 15.9 Hz), 7.64-7.24 (11H, m), 6.92-6.84 (2H, m), 6.69 (1H, d,J 15.9 Hz), 5.67 (1H, d, J 8.1 Hz), and 3.50 (3H, s). Anal. Calcd. forC₂₅ H₁₉ F₂ N₃ O₂.0.10H₂ O: C, 69.31; H, 4.47; N, 9.70. Found: C, 69.28;H, 4.57; N, 9.31%.

EXAMPLE 18 ##STR107##(+)-N-[(3R)-2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-3-(4-chlorophenyl)propanamide

m.p. 203°-205° C., [α]_(D) +99.2° (c=0.300, CH₂ Cl₂). δ_(H) (CDCl₃)7.62-7.16 (14H, m), 5.52 (1H, d, J 8.1 Hz), 3.47 (3H, s), 2.99 (2H, t, J7.7 Hz), and 2.67 (2H, t, J 7.7 Hz). Anal. Calcd. for C₂₅ H₂₂ ClN₃ O₂ :C, 69.52; H, 5.13; N, 9.73. Found: C, 69.50; H, 5.15; N, 9.72%.

EXAMPLE 19 ##STR108##E-(+)-N-[(3R)-2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-3-(2,6-dichlorophenyl)-2-propenamide

m.p. 121°-124° C., [α]_(D) +69.0° (c=0.342, CH₂ Cl₂). δ_(H) (CDCl₃) 7.79(1H, d, J 16.1 Hz), 7.64-7.15 (13H, m), 6.78 (1H, d, J 15.8 Hz), 5.69(1H, d, J 8.1 Hz), and 3.50 (3H, s). Anal. Calcd. for C₂₅ H₁₉ Cl₂ N₃O₂.0.15PhCH₃ : C, 65.44; H, 4.23; N, 8.79. Found: C, 65.40; H, 4.38; N,8.85%.

EXAMPLE 20 ##STR109##E-(+)-N-[(3R)-2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-3-[4-(trifluoromethyl)phenyl]-2-propenamide

m.p. 133°-137° C., [α]_(D) +68.7° (c=0.115, CH₂ Cl₂). δ_(H) (CDCl₃)7.72-7.25 (15H, m), 6.71 (1H, d, J 15.6 Hz), 5.67 (1H, d, J 8.1 Hz), and3.51 (3H, s). Anal. Calcd. for C₂₆ H₂₀ F₃ N₃ O₂ : C, 67.38; H, 4.35; N,9.07. Found: C, 67.38; H, 4.45; N, 8.95%.

EXAMPLE 21 ##STR110##(+)-5-Chloro-N-[(3R)-2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]indole-2-carboxamide

m.p. 160°-164° C., [α]_(D) +103.8° (c=0.160, CH₂ Cl₂). δ_(H) (CDCl₃)9.71 (1H, br s), 8.13 (1H, d, J 7.8 Hz), 7.68-7.09 (13H, m), 5.75 (1H,d, J 7.8 Hz), and 3.53 (3H, s). Anal. Calcd. for C₂₅ H₁₉ ClN₄ O₂.0.25H₂O.0.15PhCH₃ : C, 67.84; H, 4.49; N, 12.15. Found: C, 67.80; H, 4.41; N,12.07%.

EXAMPLE 22 ##STR111##(+)-N-[(3R)-2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-2,2-diphenylethanamide

m.p. 200°-201° C., [α]_(D) +97.0° (c=0.168, CH₂ Cl₂). δ_(H) (CDCl₃)7.60-7.22 (20H, m), 5.58 (1H, d, J 8.1 Hz), 5.08 (1H, s), and 3.44 (3H,s). Anal. Calcd. for C₃₀ H₂₅ N₃ O₂.0.15PhCH₃ : C, 78.79; H, 5.55; N,8.88. Found: C, 78.81; H, 5.63; N, 9.07%.

EXAMPLE 23 ##STR112##(+)-N-[(3R)-2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-3-(2,4-difluorophenyl)propanamide

m.p. 79°-81° C., [α]_(D) +92.9° (c=0.105, CH₂ Cl₂). δ.sub. H (CDCl₃)7.62-7.56 (3H, m), 7.50-7.19 (8H, m), 6.82-6.76 (2H, m), 5.52 (1H, d, J8.1 Hz), 3.47 (3H, s), 3.01 (2H, t, J 7.6 Hz), and 2.69 (2H, m). Anal.Calcd. for C₂₅ H₂₁ F₂ N₃ O₂ : C, 69.27; H, 4.88; N, 9.69. Found: C,68.96; H, 4.99; N, 9.47%.

EXAMPLE 24 ##STR113##(+)-N-[(3R)-2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-2-phenylethanamide

m.p. 241°-242° C. (dec.), [α]_(D) +85.5° (c=0.159, CH₂ Cl₂). δ_(H)(CDCl₃) 7.59-7.55 (3H, m), 7.46-7.22 (12H, m), 5.51 (1H, d, J 8.1 Hz),3.72 (2H, s), and 3.44 (3H, s). Anal. Calcd. for C₂₄ H₂₁ N₃ O₂.0.55H₂ O:C, 73.28; H, 5.66; N, 10.68. Found: C, 73.25; H, 5.38; N, 10.47%.

EXAMPLE 25 ##STR114##(+)-N-[(3R)-2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-3-(2-chlorophenyl)propanamide

m.p. 158.5°-159.5° C., [α]_(D) +95.8° (c=0.224, CH₂ Cl₂). δ_(H) (CDCl₃)7.62-7.57 (3H, m), 7.47-7.16 (11H, m), 5.55 (1H, d, J 8.1 Hz), 3.47 (3H,s), 3.14 (2H, t, J 7.9 Hz), and 2.75-2.69 (2H, m). Anal. Calcd. for C₂₅H₂₂ ClN₃ O₂.0.15H₂ O: C, 69.09; H, 5.17; N, 9.67. Found: C, 69.05; H,5.12; N, 9.63%.

EXAMPLE 26 ##STR115##(+)-N-[(3R)-2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-3-[4-(trifluoromethyl)phenyl]propanamide

m.p. 175°-176° C., [α]_(D) +86.5° (c=0.141, CH₂ Cl₂). δ_(H) (CDCl₃)7.62-7.54 (5H, m), 7.47-7.22 (9H, m), 5.52 (1H, d, J 8.1 Hz), 3.47 (3H,m), 3.08 (2H, t, J 7.6 Hz), and 2.72 (2H, m). Anal. Calcd. for C₂₆ H₂₂F₃ N₃ O₂.0.80H₂ O: C, 65.08; H, 4.93; N, 8.76. Found: C, 65.03; H, 4.63;N, 8.72%.

EXAMPLE 27 ##STR116##(+)-N-[(3R)-2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-2-[4-(trifluoromethyl)phenyl]ethanamide

m.p. 224°-226° C., [α]_(D) +68.0° (c=0.153, CH₂ Cl₂). δ_(H) (CDCl₃)7.63-7.55 (4H, m), 7.51-7.33 (8H, m), 7.26-7.23 (2H, m), 5.51 (1H, d, J8.1 Hz), 3.77 (2H, s), and 3.46 (3H, s). Anal. Calcd. for C₂₅ H₂₀ F₃ N₃O₂ : C, 66.51; H, 4.47; N, 9.31. Found: C, 66.46; H, 4.36; N, 9.10%.

EXAMPLE 28 ##STR117##(+)-N-[(3R)-2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-3-[3-(trifluoromethyl)phenyl]propanamide

m.p. 135°-136° C., [α]_(D) +78.8° (c=0.134, CH₂ Cl₂). δ_(H) (CDCl₃)7.62-7.56 (3H, m), 7.49-7.22 (11H, m), 5.53 (1H, d, J 8.1 Hz), 3.47 (3H,s), 3.08 (2H, t, J 7.3 Hz), and 2.72 (2H, m). Anal. Calcd. for C₂₆ H₂₂F₃ N₃ O₂ : C, 67.09; H, 4.76; N, 9.03. Found: C, 67.03; H, 4.73; N,9.13%.

EXAMPLE 29 ##STR118##(+)-3-Cyclohexyl-N-[(3R)-2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]propanamide

m.p. 144.5°-145.5° C., [α]_(D) +83.1° (c=0.116, CH₂ Cl₂). δ_(H) (CDCl₃)7.62-7.56 (3H, m), 7.46-7.21 (7H, m), 5.55 (1H, d, J 8.3 Hz), 3.48 (3H,s), 2.41-2.36 (2H, m), 1.77-1.58 (7H, m), 1.31-1.16 (4H, m), and0.98-0.90 (2H, m). Anal. Calcd. for C₂₅ H₂₉ N₃ O₂ : C, 74.41; H, 7.24;N, 10.41. Found: C, 74.46; H, 7.27; N, 10.58%.

EXAMPLE 30 ##STR119##(+)-N-[(3R)-2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-3-[2-(trifluoromethyl)phenyl]propanamide

m.p. 110°-113° C., [α]_(D) +79.2° (c=0.376, CH₂ Cl₂). δ_(H) (CDCl₃)7.65-7.57 (4H, m), 7.50-7.22 (10H, m), 5.55 (1H, d, J 8.0 Hz), 3.47 (3H,s), 3.20 (2H, t, J 7.9 Hz), and 2.70 (2H, dt, J 7.9, 3.3 Hz). Anal.Calcd. for C₂₆ H₂₂ F₃ N₃ O₂ : C, 67.09; H, 4.76; N, 9.03. Found: C,66.97; H, 4.76; N, 8.93%.

EXAMPLE 31 ##STR120##(+)-N-[(3R)-2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-3-(4-cyanophenyl)propanamide

m.p. 81°-85° C., [α]_(D) +91.0° (c=0.111, CH₂ Cl₂). δ_(H) (CDCl₃)7.64-7.55 (4H, m), 7.48-7.16 (10H, m), 5.50 (1H, d, J 8.3 Hz), 3.47 (3H,s), 3.08 (2H, t, J 7.6 Hz), and 2.74-2.69 (2H, m). Anal. Calcd. for C₂₆H₂₂ N₄ O₂.0.60H₂ O.0.50PhCH₃ : C, 73.93; H, 5.62; N, 11.69. Found: C,73.98; H, 5.61; N, 11.71%.

EXAMPLE 32 ##STR121##(+)-N-[(3R)-2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-3-(3-chlorophenyl)propanamide

m.p. 157°-159° C., [α]_(D) +90.7° (c=0.134, CH₂ Cl₂). δ_(H) (CDCl₃)7.62-7.57 (3H, m), 7.47-7.12 (11H, m), 5.53 (1H, d, J 8.1 Hz), 3.47 (3H,s), 3.00 (2H, t, J 7.3 Hz), and 2.71-2.66 (2H, m). Anal. Calcd. for C₂₅H₂₂ ClN₃ O₂.0.55H₂ O: C, 67.96; H, 5.27; N, 9.51. Found: C, 67.99; H,5.18; N, 9.26%.

EXAMPLE 33 ##STR122##E-(+)-N-[(3R)-2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-3-(2-bromophenyl)-2-propenamide

m.p. 113°-116° C., [α]_(D) +44.2° (c=0.113, CH₂ Cl₂). δ_(H) (CDCl₃) 8.03(1H, d, J 15.6 Hz), 7.64-7.16 (14H, m), 6.57 (1H, d, J 15.6 Hz), 5.68(1H, d, J 8.1 Hz), and 3.50 (3H, s). Anal. Calcd. for C₂₅ H₂₀ BrN₃O₂.0.60H₂ O.0.30PhCH₃ : C, 63.48; H, 4.58; N, 8.19. Found: C, 63.49; H,4.38; N, 8.19%.

EXAMPLE 34 ##STR123##E-(+)-N-[(3R)-2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-3-(3-bromophenyl)-2-propenamide

m.p. 221°-223 d° C., [α]_(D) +65.5° (c=0.206, CH₂ Cl₂). δ_(H) (CDCl₃)7.69 (1H, br s), 7.64-7.57 (4H, m), 7.51-7.37 (6H, m), 7.29-7.19 (4H,m), 6.62 (1H, d, J 15.6 Hz), 5.66 (1H, d, J 8.1 Hz), and 3.50 (3H, s).Anal. Calcd. for C₂₅ H₂₀ BrN₃ O₂.0.35H₂ O.0.20PhCH₃ : C, 63.54; H, 4.46;N, 8.42. Found: C, 63.50; H, 4.39; N, 8.42%.

EXAMPLE 35 ##STR124##E-(+)-N-[(3R)-2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-3-(4-iodophenyl)-2-propenamide

m.p. 137°-140° C., [α]_(D) +67.9° (c=0.268, CH₂ Cl₂). δ_(H) (CDCl₃)7.75-7.72 (2H, m), 7.64-7.36 (8H, m), 7.29-7.16 (5H, m), 6.63 (1H, d, J15.6 Hz), 5.66 (1H, d, J 8.1 Hz), and 3.50 (3H, m). Anal. Calcd. for C₂₅H₂₀ IN₃ O₂.0.30PhCH₃ : C, 59.29; H, 4.06; N, 7.65. Found: C, 59.29; H,3.90; N, 7.40%.

EXAMPLE 36 ##STR125##E-(+)-N-[(3R)-2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-3-(4-bromophenyl)-2-propenamide

m.p. 121°-124° C., [α]_(D) +75.6° (c=0.201, CH₂ Cl₂). δ_(H) (CDCl₃)7.64-7.57 (3H, m), 7.55-7.35 (11H, m), 7.28-7.24 (1H, m), 6.62 (1H, d, J15.6 Hz), 5.66 (1H, d, J 8.1 Hz), and 3.50 (3H, s). Anal. Calcd. for C₂₅H₂₀ BrN₃ O₂ : C, 63.30; H, 4.25; N, 8.86. Found: C, 63.50; H, 4.20; N,8.78%.

EXAMPLE 37 ##STR126##(+)-N-[(3R)-2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-4-phenylbutanamide

m.p. 65°-74° C., [α]_(D) +77.4° (c=0.155, CH₂ Cl₂). δ_(H) (CDCl₃)7.62-7.56 (3H, m), 7.46-7.19 (12H, m), 5.55 (1H, d, J 8.1 Hz), 3.47 (3H,s), 2.71 (2H, t, J 7.6 Hz), 2.42-2.37 (2H, m), and 2.09-2.01 (2H, m).Anal. Calcd. for C₂₆ H₂₅ N₃ O₂.0.30H₂ O: C, 74.91; H, 6.19; N, 10.08.Found: C, 74.93; H, 6.05; N, 10.07%.

EXAMPLE 38 ##STR127##(+)-N-[(3R)-2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-5-methyl-3-phenylisoxazole-4-carboxamide

m.p. 123°-126° C., [α]_(D) +122.0° (c=0.199, CH₂ Cl₂). δ_(H) (CDCl₃)7.79-7.76 (2H, m), 7.62-7.32 (11H, m), 7.26-7.21 (2H, m), 5.61 (1H, d, J7.9 Hz), 3.42 (3H, s), and 2.76 (3H, s). Anal. Calcd. for C₂₇ H₂₂ N₄O₃.0.40H₂ O: C, 70.85; H, 5.02; N, 12.24. Found: C, 70.84; H, 4.91; N,11.92%.

EXAMPLE 39 ##STR128##(+)-N-[(3R)-2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-3-(3-cyanophenyl)propanamide

m.p. 110°-112° C., [α]_(D) +84.2° (c=0.202, CH₂ Cl₂). δ_(H) (CDCl₃)7.63-7.22 (14H, m), 5.51 (1H, d, J 8.1 Hz), 3.47 (3H, s), 3.06 (2H, t, J7.8 Hz), and 2.74-2.68 (2H, m). Anal. Calcd. for C₂₆ H₂₂ N₄ O₂.0.50H₂ O:C, 72.37; H, 5.37; N, 12.98. Found: C, 72.52; H, 5.12; N, 12.59%.

EXAMPLE 40 ##STR129##(+)-N-[(3R)-2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]cyclohexanethanamide

m.p. 144°-146° C., [α]_(D) +72.1° (c=1.000, MeOH). Anal. Calcd. for C₂₄H₂₇ N₃ O₂.0.20H₂ O: C, 73.33: H, 7.03; N, 10.69. Found: C, 73.27; H,7.02; N, 10.76%.

EXAMPLE 41 ##STR130##(+)-4-Cyclohexyl-N-[(3R)-2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]butanamide

[α]_(D) +57.7° (c=0.440, MeOH). Anal. Calcd. for C₂₆ H₃₁ N₃ O₂ : C,74.79; H, 7.48; N, 10.06. Found: C, 74.8;0 H, 7.78; N, 10.05%.

EXAMPLE 42 ##STR131##(+)-N-[(3R)-2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-4-methylpentanamide

m.p. 123°-125° C., [α]_(D) +66.8° (c=0.500, MeOH). Anal. Calcd. for C₂₂H₂₅ N₃ O₂.0.45H₂ O: C, 71.12: H, 7.03; N, 11.31. Found: C, 71.08: H,6.81; N, 11.42%.

EXAMPLE 43 ##STR132##(+)-N-[(3R)-2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-2,3-dihydrobenzofuran-2-carboxamide

Diisopropylethylamine (0.3 mL, 223 mg, 1.72 mmol) was added to astirred, cooled (0° C.) solution of3(R)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one (J.Org. Chem. 1987, 52, 3232-3239) (400 mg, 1.5 mmol),2,3-dihydrobenzofuran-2-carboxylic acid (274 mg, 1.7 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (583 mg, 3.0mmol), and 1-hydroxybenzotriazole (479 mg, 3.1 mmol) in DMF (4.5 mL).The mixture was stirred at room temperature for 18 h., poured intoaqueous hydrochloric acid (3M, 12 mL) and extracted with ethyl acetate(3×20 mL). The combined organic fractions were washed with saturatedaqueous sodium hydrogen carbonate (20 mL) and brine (20 mL), dried(MgSO₄) and evaporated under reduced pressure. The residue wascrystallized from 2-chloro-2-methylpropane/hexane to give(+)-N-[(3R)-2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-2,3-dihydrobenzofuran-2-carboxamide as acolorless solid (156 mg, 25%), m.p. 141°-180° C., [α]_(D) +127.1°(c=0.425, CHCl₃).

δ_(H) (CDCl₃) (3:1 Mixture of diastereoisomers) 8.44 (1H, m), 7.65-6.91(13H, m), 5.52 (1H, m), 5.28 (1H, m), and 3.70-3.40 (5H, m). Anal.Calcd. for C₂₅ H₂₁ N₃ O₃.0.25 Hexane C, 73.50; H, 5.70; N, 9.71. Found:C, 74.12; H, 5.57; N, 9.71%.

EXAMPLE 44(+)-N-[(3R)-2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-1'-(1,1-dimethylethoxycarbonyl)spiro(cyclohexan-4,4'-piperidine)-1-carboxamide

Step A: ##STR133##

Diethyl 1-benzylpiperidine-4,4-diacetate

Ethanol (120 mL) was cooled in ice and ammonia bubbled through to give asaturated solution. 1-Benzyl-4-piperidone (40.0 g, 211 mmol) and ethylcyanoacetate (47.8 g, 423 mmol) were added, the reaction vesselstoppered and stored at 0° C. overnight. The solid was collected, washedwith ethanol and other and dried in vacuo to give a yellow solid (68.86g). The solid (58.86 g) was dissolved in a mixture of sulfuric acid (70mL, 98%) and water (60 mL) and heated under reflux for three days themixture cooled and most of the water evaporated. The residue wasazeotroped with ethanol (4×750 mL), further ethanol (500 mL) added andthe mixture heated under reflux for 20 h, cooled in ice and sodiumcarbonate (100 g) added slowly with vigorous stirring. The ethanol wasevaporated under reduced pressure, water (800 mL) added and the mixtureextracted with methylene chloride (3×400 mL). The combined organicextracts were dried (Na₂ SO₄) and the solvent evaporated to give diethyl1-benzylpiperidine-4,4-diacetate (37.51 g). A small portion of this waspurified by flash column chromatography.

NMR (300 MHz, CDCl₃) δ: 7.2-7.4 (m, 5H), 4.11 (q, J=7.3 Hz, 4H), 3.50(s, 2H), 2.56 (s, 4H), 2.4 (m, 4H), 1.7 (m, 4H), 1.24 (t, J=7.3 Hz, 6H).

Step B: ##STR134##

1-Benzylpiperidine-4,4-diethanol

A solution of the diester (12.2 g, 35 mmol) in ether (25 mL) was addedto a cooled (-30° C.) and stirred suspension of LiAlH₄ (2.1 g, 55 mmol)in ether (400 mL), under argon. THF (60 mL) was added and the reactionmixture allowed to warm to room temperature. After recooling to 0° C.,water (2.2 mL), 1M NaOH (4.4 mL) and water (5 mL) were added, thereaction mixture stirred vigorously for 30 min and the solid filteredoff, washing well with ether. The combined filtrates were evaporated toafford a white solid which was tritutrated with ether to give 8 g of1-benzylpiperidine-4,4-diethanol.

m.p. 75°-78° C. NMR (300 MHz, CDCl₃) δ: 7.2-7.4 (m, 5H), 3.7 (t, J=6.8Hz, 4H), 3.52 (s, 2H), 2.7 (brs, 2H), 2.43 (m, 4H), 1.66 (t, J=6.8 Hz,4H), 1.5 (m, 4H).

Step C: ##STR135##

1-t-Butoxycarbonylpiperidine-4,4-diethanol

The benzylamine (2.07 g, 7.9 mmol) was dissolved in methanol (60 mL),BOC₂ O (1.72 g, 7.9 mmol) added and the mixture hydrogenated at 50 psiover 10% palladium hydroxide on charcoal (200 mg) for 18 hours. Thereaction mixture was filtered through celite, washed with methanol andthe filtrate evaporated to give1-t-butoxy-carbonylpiperidine-4,4-diethanol (2.0 g).

NMR (300 MHz, CDCl₃) δ: 3.7 (m, 4H), d 3.3 (m, 6H), 1.65 (t, J=6.8 Hz,4H), 1.41 (s, 9H).

Step D: ##STR136##

1-t-Butoxycarbonylpiperidine-4,4-diethanol, bis(methanesulfonate)

The diol (2.41 g, 8.9 mmol) was dissolved in dichloromethene (50 mL),the solution cooled to -20° C. under argon before addition oftriethylamine (3.7 mL, 26 mmol) and methanesulfonyl chloride (1.6 mL, 20mmol). After 30 min., the reaction mixture was poured into ice cold 10%citric acid and extracted with ether (×3). The combined extracts werewashed with water, saturated NaHCO₃ and brine, dried (MgSO₄) and thesolvent evaporated to afford1-t-butoxy-carbonylpiperidine-4,4-diethanol, bis(methanesulfonate) (3.2g).

NMR (300 MHz, CDCl₃) δ: 4.32 (t, J=7.1 Hz, 4H), 3.4 (m, 4H), 3.04 (s,6H), 1.89 (t, J=7.1 Hz, 4H).

Step E: ##STR137##

Diethyl 3-t-butyloxycarbonyl-3-azaspiro[5.5]undecane-9,9-dicarboxylate

To a slurry of 60% NaH (2.04 g, 0.51 mole) in toluene (160 mL), underargon, was slowly added diethyl malonate (3.72 mL, 24.3 mmol). Themixture was cooled to 0° C. and the bis-mesylate 1 (7.0 g, 16.3 mmol)added as a solid and the mixture heated to reflux for 18 hours. Thereaction was quenched into 10% citric acid (100 mL) and the productextracted with CH₂ Cl₂ (2×150 mL). The extracts were dried (Na₂ SO₄),concentrated to an oil, and chromatographed on silica to give 3.83 g(60%) of diethyl3-t-butyloxycarbonyl-3-azaspiro[5.5]undecane-9,9-dicarboxylate.

1H NMR (CDCl₃) δ: 1.22 (t, 6H), 1.4 (s, 9H), 2.0 (m, 4H), 3.35 (m, 4H),4.2 (q, 4H).

Step F: ##STR138##

3-t-Butyloxycarbonyl-3-azaspiro[5.5]undecane-9-carboxylic acid

To a solution of the diester 2 (3.69 g, 0.0093 m) in THF (50 mL) wasadded 1N LiOH (47 mL). The reaction was stirred for 3 days at 25° C.,diluted with water (50 mL) and pH adjusted to 2.2 with KHSO₄. Theproduct was extracted into ethyl acetate (2×75 mL), dried (Na₂ SO₄), andconcentrated to a foam (3.5 g). The solid was melted in a flask at 140°C. for 2 hours, cooled and the oil dissolved in THF (15 mL), 1N LiOH (10mL) added and mixture stirred overnight at 30° C. The reaction wasconcentrated to remove THF, diluted with water (20 mL) and washed withdiethyl ether (10 mL). The pH was adjusted to 2.5 with KHSO₄ and productextracted (3×50 mL) with ethyl acetate. The extracts were dried (Na₂SO₄), filtered and concentrated to yield3-t-butyloxycarbonyl-3-azaspiro[5.5]undecane-9-carboxylic acid as a foam(2.48 g, 90%).

¹ H NMR (CDCl₃, partial) δ: 1.45 (s, 9H), 3.4 (m, 4H).

Employing the procedure substantially as described in Example 43 butsubstituting an appropriate acid for the2,3-dihydrobenzofuran-2-carboxylic acid, the following compounds wereprepared:

Step G: ##STR139##

(+)-N-[(3R)-2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-1'-(1,1-dimethylethoxycarbonyl)spiro(cyclohexan-4,4'-piperidine)-1-carboxamide

m.p. 135°-138° C., [α]_(D) +58.8° (C=0.925, CHCl₃). δ_(H) (CDCl₃)7.61-7.23 (10H, m), 5.54 (1H, d, J 9.0 Hz), 3.47 (3H, s), 3.37 (4H, m),2.28 (1H, m), and 1.81-1.18 (21H, s). Anal. Calcd. for C₃₂ H₄₀ N₄ O₄ :C, 70.56; H, 7.40; N, 10.29. Found: C, 70.21; H, 7.40; N, 10.16%.

EXAMPLE 45 ##STR140##(+)-N-[(3R)-2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-3-(furan-2-yl)propanamide

m.p. 115°-118° C., [α]_(D) +65.8° (c=0.800, CHCl₃). δ_(H) (CDCl₃)7.62-7.26 (11H, m), 6.28 (1H, dd, J 3.2, 2.0 Hz), 6.08 (1H, dd, J 3.2,0.7 Hz), 5.58 (1H, d, J 8.1 Hz), 3.48 (3H, s), 3.04 (2H, t, J 7.6 Hz),and 2.75 (2H, m). Anal. Calcd. for C₂₃ H₂₁ N₃ O₃.0.3 Hexane: C, 72.07;H, 6.15; N, 10.17. Found: C, 71.78; H, 6.30; N, 9.77%.

EXAMPLE 46 ##STR141##(+)-N-[(3R)-2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-4-(2-thienyl)butanamide

m.p. 170°-180° C., [α]_(D) +63.5° (c=1.000, MeOH). Anal. Calcd. for C₂₄H₂₃ N₃ O₂ S.0.95H₂ O: C, 66.32; H, 5.77; N, 9.67. Found: C, 66.32; H,5.34; N, 9.40%.

EXAMPLE 47 ##STR142##(+)-N-[(3R)-2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]cyclohexylcarboxamide

m.p. 213°-214° C., [α]_(D) +62.4° (c=1.000, MeOH). Anal. Calcd. for C₂₃H₂₄ N₃ O₂ : C, 73.77; H, 6.46; N, 11.22. Found: C, 73.86; H, 6.81; N,11.15%.

EXAMPLE 48 ##STR143##(E)-(+)-N-[(3R)-2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-3-(3,4-methylenedioxyphenyl)-2-propenamide

m.p. 143°-145° C., [α]_(D) +62.3° (C=0.960, MeOH). Anal. Calcd. for C₂₅H₂₁ N₃ O₄.0.10H₂ O.0.20Et₂ O: C, 69.78; H, 5.27; N, 9.46. Found: C,69.78; H, 4.98; N, 9.28%.

EXAMPLE 49 ##STR144##(+)-N-[(3R)-2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-2-quinoxalinecarboxamide

[α]_(D) +85.8° (c=0.360, MeOH). Anal. Calcd. for C₂₅ H₁₉ N₅ O₂ : C,69.96; H, 4.90; N, 15.33. Found: C, 69.95; H, 4.72; N, 15.25%.

EXAMPLE 50(+)-N-[(3R)-2,3-Dihydro-2-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-2-(phenylamino)acetamide

Step. A: ##STR145##

N-[(3R)-2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-2-bromoacetamide

Bromoacetyl bromide (165 μL, 383 mg, 1.9 mmol) was added to an icecooled solution of3(R)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one (J.Org. Chem. 1987, 52, 3232-3239) (500 mg, 1.88 mmol) and triethylamine(264 μL, 192 mg, 1.9 mmol) in methylene chloride (10 mL) and the mixturewas stirred at room temperature for 1 h. The mixture was washed withwater (3×10 mL), dried (MgSO₄) and the solvent was evaporated underreduced pressure to giveN-[(3R)-2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-2-bromoacetamideas a colorless foam (760 mg, 100%).

δ_(H) (CDCl₃) 8.24 (1H, d, J 7.8 Hz), 7.64-7.24 (9H, m), 5.48 (1H, d, J7.8 Hz), 4.00 (2H, m), and 3.50 (3H, s).

Step B: ##STR146##

(+)-N-[(3R)-2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-2-(phenylamino)acetamide

Aniline (297 μL, 304 mg, 3.26 mmol) was added to a solution ofN-[(3R)-2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-2-bromoacetamide(600 mg, 1.55 mmol) in ethanol (25 mL) and the mixture was heated underreflux for 24 h. The mixture was cooled and the solid was collected andrecrystallized from ethanol (20 mL) to give(+)-N-[(3R)-2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-2-(phenylamino)acetamideas a colorless solid (500 mg, 81%), m.p. 245°-246° C., [α]_(D) +119°(C=0.850, CHCl₃).

δ_(H) (CDCl₃) 8.26 (1H, d, J 8.3 Hz), 7.63-7.20 (12H, m), 6.81 (1H, t, J7.3 Hz), 6.72 (2H, d, J 7.6 Hz), 5.56 (1H, d, J 8.3 Hz), 3.95 (2H, d, J1.5 Hz), and 3.45 (3H, s). Anal. Calcd. for C₂₄ H₂₂ N₄ O₂ : C, 72.34; H,5.57; N, 14.06. Found: C, 72.37; H, 5.59; N, 14.32%.

Employing the procedure substantially as described above, butsubstituting 2-chloroaniline or 4-(trifluoromethyl)aniline for theaniline, the following compounds were prepared:

EXAMPLE 51 ##STR147##(+)-N-[(3R)-2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-2-(2-chlorophenylamino)acetamide

m.p. 222°-224° C., [α]_(D) +111° (c=0.973, CHCl₃). δ_(H) (CDCl₃) 8.15(1H, d, J 8.3 Hz), 7.60-7.16 (12H, m), 6.71 (2H, m), 5.57 (1H, d, J 8.3Hz), 4.01 (2H, d, J 2.7 Hz), and 3.45 (3H, s). Anal. Calcd. for C₂₄ H₂₁ClN₄ O₂ : C, 66.59; H, 4.89; N, 12.94. Found: C, 66.40; H, 4.94; N,12.92%.

EXAMPLE 52 ##STR148##(+)-N-[(3R)-2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-2-[4-(trifluoromethyl)phenylamino]acetamide

m.p. 218°-219° C., [α]_(D) +91.9° (c=0.419, CHCl₃). δ_(H) (CDCl₃) 8.13(1H, d, J 9.0 Hz), 7.70-7.25 (12H, m), 6.72 (2H, d, J 8.7 Hz), 5.60 (1H,d, J 9.0 Hz), 4.05 (2H, m), and 3.50 (3H, s). Anal. Calcd. for C₂₅ H₂₁F₃ N₄ O₂.0.7H₂ O: C, 62.68; H, 4.71: N, 11.69. Found: C, 62.47; H, 4.32;N, 11.44%.

EXAMPLE 53 ##STR149##(+)-N-[(3R)-2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-2-(phenoxy)acetamide

Phenol (104 mg, 1.1 mmol) was added to a suspension of sodium hydride(60% dispersion in mineral oil, 44 mg, 1.1 mmol) in toluene (10 mL).When hydrogen evolution had stopped,N-[(3R)-2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-2-bromoacetamide(400 mg, 1.04 mmol) was added and the mixture was stirred at roomtemperature for 18 h. The mixture was washed with water (3×15 mL), dried(MgSO₄) and the solvent was evaporated under reduced pressure. Theresidue was triturated with 2-propanol and the solid was collected andrecrystallized from 2-propanol (5 mL) to give(+)-N-[(3R)-2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-2-(phenoxy)acetamideas a colorless solid (112 mg, 27%), m.p. 126°-128° C., [α]_(D) +81.6(C=0.692, CHCl₃).

δ_(H) (CDCl₃) 8.49 (1H, d, J 8.2 Hz), 7.64-7.01 (14H, m), 5.61 (1H, d, J8.2 Hz), 4.65 (1H, d, J 14.6 Hz), 4.58 (1H, d, J 14.6 Hz), and 3.50 (3H,s). Anal. Calcd. for C₂₄ H₂₁ N₃ O₃ : C, 72.17; H, 5.30; N, 10.52. Found:C, 71.84; H, 5.25; N, 10.41%.

Employing the procedure substantially as described above, butsubstituting 2,4-dichlorophenol, thiophenol or 2,4-dichlorothiophenolfor the phenol, the following compounds were prepared:

EXAMPLE 54 ##STR150##(+)-N-[(3R)-2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-2-(2,4-dichlorophenoxy)acetamide

m.p. 206° C., [α]_(D) +31.1° (c=0.289, CHCl₃). δ_(H) (CDCl₃) 8.75 (1H,d, J 9.0 Hz), 7.65-7.20 (11H, m), 6.90 (1H, d, J 8.7 Hz), 5.60 (1H, d, J9.0 Hz), 4.65 (2H, m), and 3.50 (3H, s). Anal. Calcd. for C₂₄ H₁₉ Cl₂ N₃O₃.0.3H₂ O: C, 60.85; H, 4.17; N, 8.87. Found: C, 60.80; H, 4.00; N,8.87%.

EXAMPLE 55 ##STR151##(+)-N-[(3R)-2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-2-(phenylthio)acetamide

[α]_(D) +104.9° (c=0.316, CHCl₃). δ_(H) (CDCl₃) 8.50 (1H, d, J 9.0 Hz),7.60-7.20 (14H, m), 5.50 (1H, d, J 9.0 Hz), 3.75 (2H, m), and 3.45 (3H,s). Anal. Calcd. for C₂₄ H₂₁ N₃ O₂ S: C, 69.37; H, 5.10; N, 10.11.Found: C, 68.98; H, 5.06; N, 9.76%.

EXAMPLE 56 ##STR152##(+)-N-[(3R)-2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-2-(2,4-dichlorophenylthio)acetamide

[α[_(D) +97.4° (c=0.286, CHCl₃). δ_(H) (CDCl₃) 8.35 (1H, d, J 9.0 Hz),7.70-7.20 (12H, m), 5.50 (1H, d, J 9.0 Hz), 3.70 (2H, m), and 3.50 (3H,s). Anal. Calcd. for C₂₄ H₁₉ Cl₂ N₃ O₂ S: C, 59.51; H, 3.95; N, 8.67.Found: C, 59.32; H, 3.95; N, 8.65%.

EXAMPLE 57 ##STR153##(+)-N-[(3R)-2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-3-(phenylamino)propanamide

3-Bromopropionyl chloride (2.01 mL, 3.428 g, 20 mmol) was added to anice cooled solution of3(R)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one (J.Org. Chem. 1987, 52, 3232-3239) (5.0 g, 18.8 mmol) and triethylamine(2.79 mL, 2.02 mg, 20 mmol) in methylene chloride (85mL) and the mixturewas stirred at room temperature for 18 h. The mixture was washed withsaturated aqueous sodium hydrogen carbonate (85 mL), water (2×85 mL),and brine (85 mL), dried (MgSO₄) and the solvent was evaporated underreduced pressure. A sample (0.5 g, 1.25 mmol) was dissolved in ethanol(25 mL), aniline (230 μL, 233 mg, 2.5 mmol) was added and the mixturewas heated under reflux for 70 h. The mixture was cooled and the solidwas collected and recrystallized from ethanol to give(+)-N-[(3R)-2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-3-(phenylamino)propanamide as acolorless solid, m.p. 218°-221° C., [α]_(D) +58.2° (c=0.585, CHCl₃).

δ_(H) (CDCl₃) 7.60-6.71 (16H, m), 5.54 (1H, d, J 8.1 Hz), 3.54 (2H, t, J6.1 Hz), 3.52 (3H, s), and 2.70 (2H, m). Anal. Calcd. for C₂₅ H₂₄ N₄O₂.0.5EtOH: C, 71.70; H, 6.25; N, 12.87. Found: C, 71.42; H, 5.98; N,12.84%.

EXAMPLE 58 ##STR154##(+)-1-[(3R)-2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-3-(2,4-dichlorophenyl)urea

2,4-Dichlorophenylisocyanate (188 mg, 1.0 mmol) was added to a solutionof 3(R)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one(J. Org. Chem. 1987, 52, 3232-3239) (265 mg, 1.0 mmol) intetrahydrofuran (20 mL). The mixture was stirred at room temperature for18 h. and the solvent was evaporated under reduced pressure. The residuewas purified by flash column chromatography on silica gel, eluting withCH₂ Cl₂ /MeOH (99.5:0.5) and the residue was crystallized from CH₂ Cl₂/hexane to give(+)-1-[(3R)-2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-3-(2,4-dichlorophenyl)ureaas a colorless solid, m.p. 215°-216.5° C., [α]_(D) +76.2° (c=0.261,CHCl₃).

δ_(H) (CDCl₃) 8.10 (1H, d, J 9.0 Hz), 7.65-6.95 (13H, m), 5.50 (1H, d, J9.0 Hz), and 3.50 (3H, s). Anal. Calcd. for C₂₃ H₁₈ Cl₂ N₄ O₂.0.3H₂ O:C, 60.22; H, 4.09; N, 12.21. Found: C, 60.28; H, 3.89; N, 12.10%.

EXAMPLE 59 ##STR155##(-)-3-Cyclohexyl-N-[(3R)-2,3-dihydro-1-methyl-2-oxo-4-oxido-5-phenyl-1H-1,4-benzodiazepin-3-yl]propanamide

3-Chloroperoxybenzoic acid (80%, 0.32 g, 1.5 mmol) was added to asolution of(+)-3-cyclohexyl-N-[(3R)-2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]propanamide(0.60 g, 1.5 mmol) in dichloromethane (25 mL) and the mixture wasstirred at room temperature for 18 h. Further 3-chloroperoxybenzoic acid(80%, 0.1 g, 0.5 mmol) was added and the mixture was stirred for 24 h.The mixture was washed with saturated aqueous sodium hydrogen carbonate(4×25 mL), water (2×25 mL) and brine (25 mL), dried (MgSO₄) and thesolvent was evaporated under reduced pressure. The residue wasrecrystallized from toluene/hexane (65:35) to give(-)-3-cyclohexyl-N-[(3R)-2,3-dihydro-1-methyl-2-oxo-4-oxido-5-phenyl-1H-1,4-benzodiazepin-3-yl]propanamideas colorless prisms, m.p. 222°-224° C., [α]_(D) -80.7° (c=1.15, CHCl₃).

δ_(H) (CDCl₃) 7.71-7.23 (10H, m), 6.01 (1H, d, J 9.3 Hz), 3.54 (3H, s),2.48 (2H, m), and 1.76-0.89 (13H, m). Anal. Calcd. for C₂₅ H₂₉ N₃O₃.0.5H₂ O: C, 70.06; H, 7.06; N, 9.81. Found: C, 70.10; H, 6.80; N,9.79%.

EXAMPLE 60N-[2,3-Dihydro-1-(2-dimethylaminoethyl)-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-3-(2,4-dichlorophenyl)propanamide

Step A: ##STR156##

2,3-Dihydro-1-(2-dimethylaminoethyl)-5-phenyl-1H-1,4-benzodiazepin-2-one

2,3-Dihydro-5-phenyl-1H-1,4-benzodiazepin-2-one (1.00 g, 4.23 mmol) wasadded to hexane washed sodium hydride (60% dispersion in mineral oil,186 mg, 4.65 mmol) in DMF (5 mL). Further DMF (10 mL) was added and themixture was stirred at room temperature. 2-(Dimethylamino)ethyl chloridehydrochloride (0.73 g, 5 mmol) was added to hexane washed sodium hydride(60% dispersion in mineral oil, 200 mg, 5.0 mmol) in DMF (5 mL) and themixtures were combined. Potassium iodide (1 crystal) was added and themixture was stirred at 110° C. for 30 min. The solvent was evaporatedunder reduced pressure, water was added and the mixture was extractedwith ethyl acetate. The combined organic fractions were washed withwater (2×), dried (MgSO₄) and the solvent was evaporated under reducedpressure to give2,3-dihydro-1-(2-dimethylaminoethyl)-5-phenyl-1H-1,4-benzodiazepin-2-one(1.21 g, 93%).

δ_(H) (CDCl₃) 7.63-7.16 (9H, m), 4.77 (1H, d, J 10.6 Hz), 4.41 (1H, m),3.80 (1H, m), 3.78 (1H, d, J 10.6 Hz), 2.49 (2H, m), and 2.13 (6H, s).

Step B: ##STR157##

2,3-Dihydro-1-(2-dimethylaminoethyl)-3-hydroxyimino-5-phenyl-1H-1,4-benzodiazepin-2-one

2,3-Dihydro-1-(2-dimethylaminoethyl)-5-phenyl-1H-1,4-benzodiazepin-2-one(1.21 g, 3.9 mmol) was dissolved in toluene (20 mL). The mixture wascooled to -78° C. and potassium t-butoxide (1.0M solution in t-butanol,4.72 mL, 4.72 mmol) was added. The mixture was stirred at -78° C. for 20min., then isoamyl nitrite (0.63 mL, 0.55 g, 4.72 mmol) was added. Themixture was stirred at -78° C. for 90 min. then allowed to warm to roomtemperature and poured into aqueous citric acid (1M, 10 mL). The pH wasadjusted to 5.0 with aqueous sodium hydroxide then to 7.0 with saturatedaqueous sodium hydrogen carbonate. The mixture was extracted with ethylacetate (50 mL) and the organic layer was aged at room temperature. Thesolid which formed was collected and dried in vacuo to give2,3-dihydro-1-(2-dimethylaminoethyl)-3-hydroxyimino-5-phenyl-1H-1,4-benzodiazepin-2-one (0.876 g, 66%) as a solid, m.p. 232°-234° C.

δ_(H) (d₆ -DMSO) 10.90 (1H, s), 7.72-7.25 (9H, m), 4.40 (1H, m), 3.80(1H, m), 2.50 (2H, m), and 1.85 (6H, s).

Step C: ##STR158##

3-Amino-2,3-dihydro-1-(2-dimethylaminoethyl)-5-phenyl-1H-1,4-benzodiazepin-2-one

Ethyl isocyanate (320 μL, 287 mg, 4.0 mmol) was added to a mixture of2,3-dihydro-1-(2-dimethylaminoethyl)-3-hydroxyimino-5-phenyl-1H-1,4-benzodiazepin-2-one(0.91 g, 2.7 mmol) and triethylamine (0.56 mL, 0.41 g, 4.0 mmol) in THF(30 mL). The mixture was heated under reflux for 7 h., further ethylisocyanate (167 μL, 150 mg, 2.1 mmol) was added and the mixture washeated under reflux for 12 h. The mixture was cooled, the solvent wasevaporated under reduced pressure and ethyl acetate (75 mL) and water(25 mL) were added. The organic phase was washed with water (4×25 mL),dried (MgSO₄) and evaporated under reduced pressure. The residue wasdissolved in ethanol (100 mL), palladium on carbon (10%, 100 mg) wasadded and the mixture was shaken under hydrogen (50 p.s.i.) for 4.5 h.Further palladium on carbon (10%, 100 mg) was added and the mixture wasshaken under hydrogen (50 p.s.i.) for 1.5 h. The mixture was filteredand the solvent was evaporated under reduced pressure. The residue waspurified by flash column chromatography on silica gel, eluting with CH₂Cl₂ /MeOH to give3-amino-2,3-dihydro-1-(2-dimethylaminoethyl)-5-phenyl-1H-1,4-benzodiazepin-2-one(180 mg, 17%).

δ_(H) (CDCl₃) 7.75-7.17 (9H, m), 4.45 (1H, s), 4.40 (1H, m), 3.82 (1H,m), 2.47 (4H, m), and 2.08 (6H, s).

Step E: ##STR159##

N-[2,3-Dihydro-1-(2-dimethylaminoethyl)-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-3-(2,4-dichlorophenyl)propanamide

Triethylamine was added to a mixture of3-amino-2,3-dihydro-1-(2-dimethylaminoethyl)-5-phenyl-1H-1,4-benzodiazepin-2-one(180 mg, 0.6 mmol), 3-(2,4-dichlorophenyl)propanoic acid (131 mg, 0.6mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (115mg, 0.6 mmol) and 1-hydroxybenzotriazole (81 mg, 0.6 mmol) in DMF (15mL) until the pH was 9.0. The mixture was stirred at room temperaturefor 72 h. The solvent was evaporated under reduced pressure and ethylacetate was added. The mixture was was washed with water, saturatedaqueous sodium hydrogen carbonate and water, dried (MgSO₄) andevaporated under reduced pressure. The residue was triturated withacetone and recrystallized from i-PrOH/MeOH to giveN-[2,3-dihydro-1-(2-dimethylaminoethyl)-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-3-(2,4-dichlorophenyl)propanamideas a solid, m.p. 199°-201° C.

δ_(H) (CDCl₃) 7.60-7.15 (13H, m), 5.50 (1H, d, J 8.0 Hz), 4.40 (1H, m),3.80 (1H, m), 3.10 (2H, t, J 7.5 Hz), 2.70 (2H, t, J 7.5 Hz), 2.40 (2H,m), and 2.05 (6H, s). Anal. Calcd. for C₂₈ H₂₈ Cl₂ N₄ O₂ : C, 64.25; H,5.39; N, 10.70. Found: C, 64.23; H, 5.40; N, 10.61%.

EXAMPLE 61 ##STR160##(+)-3(R)-{N-[3-(4-chlorophenyl)prop-1-en-3-yl]amino}-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-onehydrochloride

A mixture of3(R)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one (J.Org. Chem. 1987, 52, 3232-3239) (265 mg, 1 mmol),E-1-chloro-4-(3-chloro-1-propenyl)benzene (281 mg, 1.5 mmol), potassiumcarbonate (276 mg, 2 mmol) and potassium iodide (25 mg, 0.15 mmol) inacetonitrile (2 mL) was heated under reflux for 4 h. The mixture wascooled and poured into ethyl acetate (10 mL) and water (5 mL). Thelayers were separated and the aqueous layer was extracted with ethylacetate (5 mL). The combined organic fractions were washed with brine,dried (Na₂ SO₄) and the solvent was evaporated under reduced pressure.The residue was purified by flash column chromatography on silica gel,eluting with EtOAc/Hexane (65:35 increasing to 100:0). The firstcompound to elute was suspended in ethanol (1 mL) and ethanolic HCl (6M,0.11 mL) was added. The mixture was stirred, then the solvent wasevaporated under reduced pressure. The residue was triturated with etherand the solid was collected and dried in vacuo to give(+)-3(R)-{N,N-bis[1-(4-chlorophenyl)propen-3-yl]amino}-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-onehydrochloride (235 mg, 39%) as a tan solid, m.p. 138°-145° C., [α]_(D)+9.2° (c=0.500, MeOH).

δ_(H) (d₆ -DMSO) 11.2 (1H, br s), 7.77-7.31 (17H, m), 6.85 (2H, br m),6.54 (2H, m), 5.20 (1H, br s), 4.60-4.00 (4H, m), and 3.46 (3H, s).Anal. Calcd. for C₃₄ H₂₉ Cl₂ N₃ O.HCl.0.10EtOH: C, 67.60; H, 5.08; N,6.92. Found: C, 67.60; H, 5.03; N, 7.03%.

The second compound to elute was suspended in ethanol (0.5 mL) andethanolic HCl (6M, 0.035 mL) was added. The mixture was stirred, thenthe solvent was evaporated under reduced pressure. The residue wastriturated with ether and the solid was collected and dried in vacuo togive(+)-3(R)-{N-[3-(4-chlorophenyl)propen-3-yl]amino}-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-onehydro-chloride (56 mg, 12%) as a yellow solid, m.p. 156°-162° C.,[α]_(D) +35° (c=0.100, MeOH).

δ_(H) (d₆ -DMSO) 10.3 (1H, br s), 10.0 (1H, br s), 7.79-7.34 (13H, m),6.78 (1H, d, J 15.9 Hz), 6.40 (1H, dt, J_(d) 15.9, J_(t) 9.0 Hz), 5.13(1H, s), 4.00 (2H, m), and 3.46 (3H, s). Anal. Calcd. for C₂₅ H₂₂ ClN₃O.HCl.0.10EtOH.0.40H₂ O: C, 65.20; H, 5.30; N, 9.05. Found: C, 65.14; H,5.09; N, 9.33%.

Employing the procedure substantially as described above, butsubstituting 1-(2-bromoethoxy)-4-nitrobenzene or 4-chlorobenzenepropanolmethanesulfonate for the E-1-chloro-4-(3-chloro-1-propenyl)benzene, thefollowing compounds were prepared:

EXAMPLE 62 ##STR161##(+)-3(S)-{N,N-Bis[2-(4-nitrophenoxy)ethyl]amino}-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-onehydrochloride

m.p. 126°-145° C. [α]_(D) +5.0° (0.100, CHCl₃). δ_(H) (d₆ -DMSO) 8.20(4H, d, J 9.2 Hz), 7.75-7.36 (9H, m), 7.08 (4H, d, J 9.2 Hz), 4.90 (1H,br s), 4.50 (4H, br s), 4.30-3.60 (5H, br m), and 3.34 (3H, s). Anal.Calcd. for C₃₂ H₂₉ N₅ O₇.HCl.0.15EtOH: C, 60.71; H, 4.87; N, 10.96.Found: C, 60.70; H, 4.87; N, 10.70%.

EXAMPLE 63 ##STR162##(+)-3(R)-{N-[3-(4-Nitrophenoxy)ethyl]amino}-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-onehydrochloride

m.p. 154°-160° C., [α]_(D) +84.6° (0.500, MeOH). δ_(H) (d₆ -DMSO) 10.2(1H, br s), 8.25 (2H, d, J 9.0 Hz), 7.83-7.41 (9H, m), 7.09 (2H, d, J9.0 Hz), 5.21 (1H, s), 4.57 (2H, m), 3.70 (2H, m), 3.47 (3H, s), and3.40 (1H, m). Anal. Calcd. for C₂₄ H₂₂ N₄ O₄.HCl.0.15EtOH.0.20H₂ O: C,61.13; H, 5.13; N, 11.74. Found: C, 61.12; H, 4.92; N, 11.64%.

EXAMPLE 64 ##STR163##(+)-3(R)-{N-[3-(4-Chlorophenyl)prop-1-yl]amino}-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-onehydrochloride

m.p. 167°-168° C., [α]_(D) +20.8° (c=0.500, MeOH). δ_(H) (d₆ -DMSO) 9.9(2H, br m), 7.78-7.26 (13H, m), 5.08 (1H, s), 3.45 (3H, s), 3.20 (1H,m), 3.00 (1H, m), 2.70 (2H, t, J 7.4 Hz), and 2.05 (2H, m). Anal. Calcd.for C₂₅ H₂₄ ClN₃ O.HCl: C, 66.08; H, 5.55; N, 9.25. Found: C, 65.81; H,5.49; N, 9.30%.

EXAMPLE 65 ##STR164## (+)-PhenylmethylN-[(3R)-2,3-dihydro-1-methyl-5-phenyl-2-thioxo-1H-1,4-benzodiazepin-3-yl]carbamate

A mixture of (+)-phenylmethylN-[(3R)-2,3-dihydro-1-methyl-5-phenyl-2-oxo-1H-1,4-benzodiazepin-3-yl]carbamate(4.0 g, 10 mmol) and2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (4.5g, 11 mmol) in toluene (100 mL) was heated under reflux for 75 min. Themixture was cooled and the volume was reduced to 30 mL by evaporationunder reduced pressure. The residue was purified by flash columnchromatography on silica gel, eluting with EtOAc/Hexane (75:25) to give(+)-phenylmethylN-[(3R)-2,3-dihydro-1-methyl-5-phenyl-2-thioxo-1H-1,4-benzodiazepin-3-yl]carbamateas a solid, m.p. 128°-131° C., [α]_(D) +22.5° (c=0.656, CHCl₃).

δ_(H) (CDCl₃) 7.65-7.26 (15H, m), 5.50 (1H, d, J 8.8 Hz), 5.14 (2H, s),and 3.86 (3H, s). Anal. Calcd. for C₂₄ H₂₁ N₃ O₂ S.0.25H₂ O: C, 68.63;H, 5.16; N, 10.01. Found: C, 68.28; H, 5.21; N, 10.06%.

Employing the procedure substantially as described above, butsubstituting phenylmethylN-[2,3-dihydro-5-phenyl-2-oxo-1H-1,4-benzodiazepin-3-yl]carbamate forthe (+)-phenylmethylN-[(3R)-2,3-dihydro-1-methyl-5-phenyl-2-oxo-1H-1,4-benzodiazepin-3-yl]carbamate,the following compound was prepared:

EXAMPLE 66 ##STR165## PhenylmethylN-[2,3-dihydro-5-phenyl-2-thioxo-1H-1,4-benzodiazepin-3-yl]carbamate

δ_(H) (d₆ -DMSO) 10.85 (1H, s), 8.42 (1H, d, J 8.6 Hz), 7.65-7.10 (14H,m), 5.10 (2H, s), and 5.05 (1H, d, J 8.6 Hz).

EXAMPLE 67 ##STR166##3-Cyclohexyl-N-(2,3-dihydro-1-methyl-5-phenyl-2-thioxo-1H-1,4-benzodiazepin-3-yl)propanamide

Hydrogen bromide was bubbled at room temperature through a solution of(+)-phenylmethylN-[(3R)-2,3-dihydro-1-methyl-5-phenyl-2-thioxo-1H-1,4-benzodiazepin-3-yl]carbamate(0.9 g, 2.1 mmol), acetic acid (5 mL) and dichloromethane (5 mL). After2 h., the solvent was evaporated under reduced pressure, ether was addedand the solid was collected and dried in vacuo. A sample (0.58 g, 1.8mmol) was suspended in THF (10 mL), triethylamine (0.24 mL, 0.18 g, 1.8mmol) was added and the mixture was stirred at room temperature for 3 h.In a separate flask, oxalyl chloride (0.20 mL, 0.29 g, 2.3 mmol) wasadded to a solution of cyclohexanepropionic acid (0.33 mL, 0.30 g, 1.9mmol) and DMF (1 drop) in THF (10 mL) and the mixture was stirred atroom temperature for 3 h. The two mixtures were combined, triethylamine(0.32 mL, 0.23 g, 2.3 mmol) was added and the mixture was stirred atroom temperature for 2.5 h. The solvent was evaporated under reducedpressure, water was added and the mixture was extracted with ethylacetate. The combined organic fractions were washed with water,saturated aqueous sodium hydrogen carbonate, water (2×) and brine, dried(Na₂ SO₄) and the solvent was evaporated under reduced pressure. Theresidue was purified by flash column chromatography on silica gel,eluting with CH₂ Cl₂ /MeOH (99.5:0.5) and the residue was recrystallizedfrom EtOAc/Hexane to give3-cyclohexyl-N-(2,3-dihydro-1-methyl-5-phenyl-2-thioxo-1H-1,4-benzodiazepin-3-yl)propanamideas a solid, m.p. 219°-221° C.

δ_(H) (CDCl₃) 7.95 (1H, br d, J 8.6 Hz), 7.65-7.30 (9H, m), 5.72 (1H, d,J 8.6 Hz), 3.87 (3H, s), 2.41 (2H, t, J 7.6 Hz), and 1.80-0.85 (1 3H,m). Anal. Calcd. for C₂₅ H₂₉ N₃ OS.0.25H₂ O: C, 70.81; H, 7.01; N, 9.91.Found: C, 70.80; H, 6.91; N, 9.95%.

Employing the procedure substantially as described above, butsubstituting phenylmethylN-[2,3-dihydro-5-phenyl-2-thioxo-1H-1,4-benzodiazepin-3-yl]carbamate forthe (+)-phenylmethylN-[(3R)-2,3-dihydro-1-methyl-5-phenyl-2-thioxo-1H-1,4-benzodiazepin-3-yl]carbamateand an appropriate acid for the cyclohexanepropionic acid, the followingcompounds were prepared:

EXAMPLE 68 ##STR167##3-Cyclohexyl-N-(2,3-dihydro-5-phenyl-2-thioxo-1H-1,4-benzodiazepin-3-yl)propanamide

m.p. 113°-119° C. δ_(H) (CDCl₃) 9.8 (1H, br s), 7.75-7.25 (10H, m), 5.75(1H, d, J 8.1 Hz), 2.41 (2H, m), and 1.80-0.85 (13H, m). Anal. Calcd.for C₂₄ H₂₇ N₃ OS.0.8CH₂ Cl₂ : C, 62.91; H, 6.09; N, 8.87. Found: C,62.88; H, 5.70; N, 9.12%.

EXAMPLE 69 ##STR168##3-Cyclohexyl-N-(2,3-dihydro-2-hydrazono-5-phenyl-1H-1,4-benzodiazepin-3yl)propanamide

Hydrazine (53 μL, 56 mg, 1.8 mmol) was added to a solution of3-cyclohexyl-N-(2,3-dihydro-1-methyl-5-phenyl-2-thioxo-1H-1,4-benzodiazepin-3-yl)propanamide(120 mg, 0.25 mmol) in methanol (3 mL). The mixture was stirred at roomtemperature for 3 h. and the solvent was evaporated under reducedpressure. Ethyl acetate was added and the mixture was washed with waterand brine, dried (Na₂ SO₄) and the solvent was evaporated under reducedpressure. The residue was purified by flash column chromatography onsilica gel, eluting with CH₂ Cl₂ /MeOH (99.5:0.5 increasing to 98:2) togive3-cyclohexyl-N-(2,3-dihydro-2-hydrazono-5-phenyl-1H-1,4-benzodiazepin-3yl)propanamideas a foam.

δ_(H) (CDCl₃) 7.55-7.00 (11H, m), 5.75 (1H, d, J 7.6 Hz), 3.50 (2H, brs), 2.37 (2H, t, J 8.0 Hz), and 1.80-0.85 (13H, m). Anal. Calcd. for C₂₄H₂₉ N₅ O.0.8CH₃ OH.0.15CH₂ Cl₂ : C, 67.82; H, 7.41; N, 15.85. Found: C,67.79; H, 7.46; N, 16.05%.

EXAMPLE 70 ##STR169## (E)- and(Z)-3-Cyclohexyl-N-(2,3-dihydro-2-hydroxyimino-5-phenyl-1H-1,4-benzodiazepin-3-yl)propanamide

A mixture of3-cyclohexyl-N-(2,3-dihydro-1-methyl-5-phenyl-2-thioxo-1H-1,4-benzodiazepin-3-yl)propanamide(740 mg, 1.83 mmol), hydroxylamine hydrochloride (140 mg, 2 mmol) andtriethylamine (280 μL, 203 mg, 2 mmol) in methanol (15 mL)/THF (15 mL)was stirred at room temperature for 3 h. The solvent was evaporatedunder reduced pressure and the residue was purified by flash columnchromatography on silica gel, eluting with CH₂ Cl₂ /MeOH (98:2). Theresidue recrystallized from ethyl acetate. The first isomer tocrystallize was recrystallized from ethyl acetate to give(E)-3-cyclohexyl-N-(2,3-dihydro-2-hydroxyimino-5-phenyl-1H-1,4-benzodiazepin-3-yl)propanamideas a solid, m.p. 196° C.

δ_(H) (d₆ -DMSO) 12.20 (1H, s), 9.00 (1H, d, J 8.0 Hz), 7.70-7.30 (10H,m), 5.45 (1H, d, J 8.0 Hz), 2.30 (2H, m), and 1.80-0.75 (13H, m).

The second isomer to crystallize was recrystallized from methanol togive(Z)-3-cyclohexyl-N-(2,3-dihydro-2-hydroxyimino-5-phenyl-1H-1,4-benzodiazepin-3-yl)propanamideas a solid, m.p. 219° C.

δ_(H) (d₆ -DMSO) 9.95 (1H, s), 8.95 (1H, s), 8.75 (1H, d, J 8.0 Hz),7.50-7.00 (9H, m), 5.70 (1H, d, J 8.0 Hz), 2.25 (2H, m), and 1.75-0.75(13H, m). Anal. Calcd. for C₂₄ H₂₈ N₄ O₂ : C, 71.26; H, 6.98; N, 13.85.Found: C, 70.89; H, 6.99; N, 13.55%.

EXAMPLE 71 ##STR170##3-Cyclohexyl-N-(2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-3yl)propanamide

Freshly prepared Raney nickel (400 mg) was added to a solution of3-cyclohexyl-N-(2,3-dihydro-1-methyl-5-phenyl-2-thioxo-1H-1,4-benzodiazepin-3-yl)propanamide(200 mg, 0.5 mmol) in ethanol (20 mL) and the mixture was stirred atroom temperature for 2 h. The mixture was filtered and the solvent wasevaporated under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel, eluting with CH₂ Cl₂ /MeOH(99.75:0.25) to give3-cyclohexyl-N-(2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-3yl)propanamideas a foam.

δ_(H) (CDCl₃) 7.60-6.80 (9H, m), 6.37 (1H, br d, J 6.6 Hz), 5.53 (1H,m), 3.60 (2H, m), 2.77 (3H, s), 2.21 (2H, t, J 8.0 Hz), and 1.85-0.80(13H, m). Anal. Calcd. for C₂₅ H₃₁ N₃ O.0.2CH₂ Cl₂ : C, 74.45; H, 7.79;N, 10.34. Found: C, 74.68; H, 7.87; N, 10.23%.

EXAMPLE 721-(2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-thieno-[2,3-e]-1.4-diazepin-3-yl)-3-(3-methyl-phenyl)urea

Step A: ##STR171##

(2-Amino-3-thienyl)phenylmethanone

Triethylamine (6.8 mL, 4.94 g, 49 mmol) was added to a heated (33° C.)mixture of β-oxobenzenepropanenitrile (18.6 g, 128 mmol) and1,2-dithiane-2,5-diol (9.8 g, 64 mmol) in ethanol (120 mL) and themixture was stirred at 50 C.° for 18 h. The mixture was cooled and thesolvent was evaporated under reduced pressure. Dichloromethane wasadded, the mixture was washed with aqueous hydrochloric acid (0.5M),aqueous sodium hydroxide (1M) and brine, dried (Na₂ SO₄) and the solventwas evaporated under reduced pressure. The residue was recrystallizedfrom acetonitrile (150 mL) to give (2-amino-3-thienyl)-phenylmethanoneas an orange solid (5.7 g, 44%).

δ_(H) (CDCl₃) 7.70-7.35 (5H, m), 6.95 (2H, br s), 6.90 (1H, d, J 6.3Hz), and 6.15 (1H, d, J 6.3 Hz).

Step B: ##STR172##

2,3-Dihydro-5-phenyl-1H-thieno[2,3-e]-1,4-diazepin-2-one

A solution of 1,3-dihydro-1,3-dioxo-2H-isoindole-2-acetyl chloride (8.6g, 38 mmol) in dichloromethane (20 mL) was added slowly to a cooled (0°C.) mixture of (2-amino-3-thienyl)phenylmethanone (6.8 g, 33 mmol),pyridine (6.34 mL, 6.20 g, 78 mmol) and 4-dimethylamino-pyridine (0.79g, 6.5 mmol) in dichloromethane (130 mL). The mixture was stirred at 0°C. for 30 min., diluted with dichloromethane (80 mL) and washed withaqueous hydrochloric acid (1M), saturated aqueous sodium hydrogencarbonate and brine. The mixture was dried (Na₂ SO₄) and the solvent wasevaporated under reduced pressure. The residue was triturated withethanol and the solid was collected and dried in vacuo to giveN-(3-benzoylthien-2-yl)-1,3-dihydro-1,3-dioxo-2H-isoindole-2-acetamideas a solid (9.8 g, 76%).

A mixture ofN-(3-benzoylthien-2-yl)-1,3-dihydro-1,3-dioxo-2H-isoindole-2-acetamide(10.9 g, 28 mmol) and hydrazine (1.9 mL, 1.94 g, 60 mmol) in THF (500mL) was heated under reflux for 4 h. The mixture was cooled, filteredand the solvent was evaporated under reduced pressure. Saturated aqueoussodium hydrogen carbonate was added and the mixture was extracted withethyl acetate. The combined organic fractions were washed with brine,dried (Na₂ SO₄) and the solvent was evaporated under reduced pressure.Acetic acid (300 mL) was added and the mixture was heated under refluxfor 15 min. The mixture was cooled and the solvent was evaporated underreduced pressure. Saturated aqueous sodium hydrogen carbonate was addedand the mixture was extracted with ethyl acetate. The combined organicfractions were washed with brine, dried (Na₂ SO₄) and the solvent wasevaporated under reduced pressure to give2,3-dihydro-5-phenyl-1H-thieno[2,3-e]-1,4-diazepin-2-one as a foam (3.5g, 52%).

δ_(H) (CDCl₃) 9.75 (1H, br s), 7.90-7.30 (5H, m), 6.87 (1H, d, J 6.0Hz), 6.82 (1H, d, J 6.0 Hz), and 4.45 (2H, s).

Step C: ##STR173##

2,3-Dihydro-1-methyl-5-phenyl-1H-thieno[2,3-e]-1,4-diazepin-2-one

Sodium hydride (60% dispersion in mineral oil, 757 mg, 11.3 mmol) wasadded to a cooled (0° C.) solution of2,3-dihydro-5-phenyl-1H-thieno[2,3-e]-1,4-diazepin-2-one (2.61 g, 10.8mmol) in DMF (7 mL). Further DMF (10 mL) was added and the mixture wasstirred for 30 min. A solution of iodomethane (0.67 mL, 1.53 g, 10.8mmol) in ether (20 mL) was added and the mixture was stirred for 1 h.The mixture was poured into water and the mixture was extracted withethyl acetate. The combined organic fractions were washed with brine,dried (Na₂ SO₄) and evaporated under reduced pressure. The residue waspurified by flash column chromatography on silica gel, eluting with CH₂Cl₂ /MeOH (95:5) to give2,3-dihydro-1-methyl-5-phenyl-1H-thieno[2,3-e]-1,4-diazepin-2-one (1.5g, 54%).

δ_(H) (CDCl₃) 7.67-7.35 (5H, m), 7.00 (1H, d, J 6.0 Hz), 6.85 (1H, d, J6.0 Hz), 4.45 (2H, br s), and 3.50 (3H, s).

Step D: ##STR174##

3-Amino-2,3-dihydro-1-methyl-5-phenyl-1H-thieno[2,3-e]-1,4-diazepin-2-one

2,3-Dihydro-1-methyl-5-phenyl-1H-thieno[2,3-e]-1,4-diazepin-2-one (1.5g, 5.8 mmol) was dissolved in toluene (30 mL). The mixture was cooled to-10° C. and potassium t-butoxide (1.7 g, 15.1 mmol) was added. Themixture was stirred at -10° C. for 15 min., then isoamyl nitrite (1.0mL, 0.87 g, 7.4 mmol) was added. The mixture was stirred at -10° C. for1 h. then allowed to warm to room temperature and poured into water (50mL) and acetic acid (3 mL). The mixture was extracted with ethyl acetateand the combined organic fractions were washed with brine, dried (Na₂SO₄) and the solvent was evaporated under reduced pressure. The residuewas purified by flash column chromatography on silica gel, eluting withEtOAc/Hexane to give2,3-dihydro-1-methyl-3-hydroxyimino-5-phenyl-1H-thieno[2,3-e]-1,4-diazepin-2-one(0.80 g, 48 %).

2,3-Dihydro-1-methyl-3-hydroxyimino-5-phenyl-1H-thieno[2,3-e]-1,4-diazepin-2-one(0.80 g, 2.8 mmol) was dissolved in ethanol (40 mL) and Raney nickel (2g) was added. The mixture was shaken under hydrogen (50 p.s.i.) for 5days, adding further Raney nickel (10 g) in portions. The mixture wasfiltered and the solvent was evaporated under reduced pressure. Theresidue was purified by flash column chromatography on silica gel,eluting with CH₂ Cl₂ /MeOH to give3-amino-2,3-dihydro-1-methyl-5-phenyl-1H-thieno[2,3-e]-1,4-diazepin-2-one(248 mg, 33%).

δ_(H) (CDCl₃) 7.50-7.30 (5H, m), 7.05 (1H, d, J 6.0 Hz), 6.85 (1H, d, J6.0 Hz), 4.57 (1H, s), 3.55 (3H, s), and 1.70 (2H, br s).

Step E: ##STR175##

1-(2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-thieno[2,3-e]-1,4-diazepin-3-yl)-3-(3-methylphenyl)urea

3-Methylphenylisocyanate (60 μL, 62 mg, 0.46 mmol) was added to asolution of3-amino-2,3-dihydro-1-methyl-5-phenyl-1H-thieno[2,3-e]-1,4-diazepin-2-one(124 mg, 0.46 mmol) in tetrahydrofuran (5 mL). The mixture was stirredat room temperature for 2 h. and the solvent was evaporated underreduced pressure. The residue was crystallized from EtOAc (4 mL) to give1-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-thieno[2,3-e]-1,4-diazepin-3-yl)-3-(3-methylphenyl)ureaas a solid (94 mg, 50%). m.p. 128°-130° C.

δ_(H) (CDCl₃) 8.70 (1H, s), 7.65-6.75 (12H, m), 5.55 (1H, d, J 9.0 Hz),3.55 (3H, s), and 2.30 (3H, s). Anal. Calcd. for C₂₂ H₂₀ N₄ O₂ S.0.25H₂O: C, 64.62; H, 4.99; N, 13.70. Found: C, 64.68; H, 4.96; N, 13.70%.

EXAMPLE 73 ##STR176##3-Cyclohexyl-N-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-thieno[2,3e]-1,4-diazepin-3-yl)propanamide

Triethylamine (75 μL, 54 mg, 0.54 mmol) was added to a mixture of3-amino-2,3-dihydro-1-methyl-5-phenyl-1H-thieno[2,3-e]-1,4-diazepin-2-one(82 mg, 0.3 mmol), cyclohexanepropanoic acid (52 μL, 47 mg, 0.3 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (58 mg, 0.3mmol) and 1-hydroxybenzotriazole (42 mg, 0.3 mmol) in DMF (1.5 mL). Themixture was stirred at room temperature for 18 h. and ethyl acetate (60mL) was added. The mixture was washed with aqueous citric acid (10%),saturated aqueous sodium hydrogen carbonate and brine, dried (Na₂ SO₄)and the solvent was evaporated under reduced pressure. The residue waspurified by flash column chromatography on silica gel, eluting withEtOAc/Hexane to give3-cyclohexyl-N-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-thieno[2,3-e]-1,4-diazepin-3-yl)propanamideas a solid (56 mg, 46%). m.p. 189° -190° C.

δ_(H) (CDCl₃) 7.65-6.85 (8H, m), 5.65 (1H, d, J 8.0 Hz), 3.55 (3H, s),2.40 (2H, t, J 7.0 Hz), and 1.80-0.85 (13H, m). Anal. Calcd. for C₂₃ H₂₇N₃ O₂ S.0.5H₂ O: C, 66.00; H, 6.74; N, 10.04. Found: C, 66.25; H, 6.76;N, 9.83%.

EXAMPLE 74 ##STR177##3-Cyclohexyl-N-(5-cyclohexyl-2,3-dihydro-2-oxo-1H-1,4-benzodiazepin-3-yl)propanamide

PhenylmethylN-[5-cyclohexyl-2,3-dihydro-2-oxo-1H-1,4-benzodiazepin-3-yl]carbamate(150 mg, 0.38 mmol) was dissolved in hydrogen bromide in acetic acid(30%, 0.5 mL). After 2 h., ether was added and the solid was collectedand dried in vacuo. THF (3 mL) and triethylamine (0.45 μL, 33 mg, 0.32mmol) were added and the mixture was stirred at room temperature for 3h. In a separate flask, oxalyl chloride (38 μL, 56 mg, 0.44 mmol) wasadded to a solution of cyclohexanepropionic acid (61 μL, 56 mg, 0.36mmol) and DMF (1 drop) in THF (2 mL) and the mixture was stirred at roomtemperature for 3 h. The two mixtures were combined, triethylamine (61μL, 44 mg, 0.44 mmol) was added and the mixture was stirred at roomtemperature for 3 h. The solvent was evaporated under reduced pressureand ethyl acetate was added. The mixture was washed with water (2×),saturated aqueous sodium hydrogen carbonate, water and brine, dried (Na₂SO₄) and the solvent was evaporated under reduced pressure. The residuewas recrystallized from i-PrOH to give3-cyclohexyl-N-(5-cyclohexyl-2,3-dihydro-2-oxo-1H-1,4-benzodiazepin-3-yl)propanamideas a solid, m.p. 133°-138° C.

δ_(H) (CDCl₃) 7.85 (1H, br s), 7.62-6.95 (5H, m), 5.40 (1H, d, J 8.7Hz), 2.77 (1H, m), 2.34 (2H, m), and 2.05-0.75 (23H, m). Anal. Calcd.for C₂₄ H₃₃ N₃ O₂.0.7C₃ H₇ OH: C, 71.64; H, 8.89; N, 9.60. Found: C,71.28; H, 8.70; N, 9.82%.

EXAMPLE 75 ##STR178##(+)-N-[(3R)-7-Amino-2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-3-(2,4-dichlorophenyl)propanamide

Step A:

5 To a mixture of3(R)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one (J.Org. Chem. 1987, 52, 3232-3239) (3.98 g, 15.0 mmol) in concentratedsulfuric acid (15 mL) cooled in an ice-bath was added dropwise asolution of potassium nitrate (2.12 g, 21.0 mmol) in concentratedsulfuric acid (6 mL). The mixture was stirred with cooling for 2 h.,then stirred at ambient temperature for 1.5 h. Ice (80 g) was added andthe mixture was basified with concentrated ammonium hydroxide to pH 9.The resulting mixture was extracted with ethyl acetate (3×220 mL). Thecombined organic fractions were washed with brine, dried (Na₂ SO₄) andthe solvent was evaporated under reduced pressure. The residue waspurified by flash column chromatography on silica gel, eluting withchloroform/methanol (97:3). The material which eluted was furtherpurified by flash column chromatography on silica gel, eluting withethyl acetete/methanol (95:5). The material which eluted was stirredunder n-butyl chloride (30 mL) and the solvent was evaporated underreduced pressure to give an inseparable mixture of3(R)-amino-1,3-dihydro-1-methyl-7-nitro-5-phenyl-2H-1,4-benzodiazepin-2-oneand3(R)-amino-1,3-dihydro-1-methyl-7-nitro-5-(2-nitrophenyl)-2H-1,4-benzodiazepin-2-one(3.81 g) in a 3:1 ratio as a yellow solid.

δ_(H) (CDCl₃) (mononitro compound) 8.43 (1H, dd, J 9, 3 Hz), 8.23 (1H,d, J 3 Hz), 7.59 (2H, m), 7.52 (2H, m), 7.44 (2H, m), 4.47 (1H, s), 3.53(3H,s), and 2.42 (2H, br s); (dinitro compound) 8.49 (1H, dd, J 9, 3),8.42 (1H, m), 8.18 (1H, d, J 3 Hz), 8.01 (1H, m), 7.67 (1H, t, J 6 Hz),7.6-7.4 (2H, m), 4.52 (1H, s), 3.56 (3H, s), and 2.42 (2H, br s).

Step B:

A solution of 3-(2,4-dichlorophenyl)propionic acid (482 mg, 2.2 mmol),DMF (0.017 mL, 0.22 mmol), and thionyl chloride (0.24 mL, 3.3 mmol) inchloroform (2.5 mL) was heated at reflux for 1 h. The solvent wasevaporated under reduced pressure to give3-(2,4-dichlorophenyl)propionyl chloride (520 mg, 100%). To a solutionof mixed3(R)-amino-1,3-dihydro-1-methyl-7-nitro-5-phenyl-2H-1,4-benzodiazepin-2-oneand3(R)-amino-1,3-dihydro-1-methyl-7-nitro-5-(2-nitrophenyl)-2H-1,4-benzodiazepin-2-one(3:1) (621 mg, 2 mmol) and triethylamine (0.305 mL, 2.2 mmol) inmethylene chloride (10 mL), was added a solution of3-(2,4-dichlorophenyl)propionyl chloride (520 mg, 2.2 mmol) in methylenechloride (1.5 mL). The mixture was stirred for 30 min., the solvent waspartially evaporated under reduced pressure, and the reaction mixturewas purified by flash column chromatography on silica gel, eluting withmethylene chloride/ether (90:10) to give a mixture of(+)-N-[(3R)-2,3-dihydro-1-methyl-7-nitro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-3-(2,4-dichlorophenyl)propanamideand(+)-N-[(3R)-2,3-dihydro-1-methyl-7-nitro-2-oxo-5-(2-nitrophenyl)-1H-1,4-benzodiazepin-3-yl]-3-(2,4-dichlorophenyl)propanamide(850 mg, 84%) in a 3:1 ratio as a solid white foam.

δ_(H) (CDCl₃) (mononitro compound) 8.45 (1H, dd, J 9, 3 Hz), 8.25 (1H, dJ 3 Hz), 7.54 (3H, m), 7.45 (2H, m), 7.38 (1H, d, J 2 Hz), 7.26-7.18(4H, m), 5.50 (1H, d, J 8 Hz), 3.52 (3H, s), 3.10 (2H, m), and 2.70 (2H,m); (dinitro compound) 8.51 (1H, dd, J 9, 3 Hz), 8.40 (1H, m), 8.21 (1H,d J 3 Hz), 7.98 (1H, m), 7.68 (1H, t, J 6 Hz), 7.60 (1H, m), 7.44 (1H,m), 7.26-7.15 (4H, m), 5.52 (1H, d, J 8 Hz), 3.55 (3H, s), 3.10 (2H, m),and 2.70 (2H, m).

Step C:

To a solution of mixedN-[(3R)-2,3-dihydro-1-methyl-7-nitro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-3-(2,4-dichlorophenyl)propanamideand(+)-N-[(3R)-2,3-dihydro-1-methyl-7-nitro-2-oxo-5-(2-nitrophenyl)-1H-1,4-benzodiazepin-3-yl]-3-(2,4-dichlorophenyl)propanamide(3:1) (770 mg, 1.5 mmol) in acetic acid (6 mL) was added dropwise inportions over 1.5 h. a solution of 15% titanium (III) chloride in 20-30%hydrochloric acid (7.8 mL, 9.0 mmol). The resulting solution was stirred30 min., basified with 20% sodium hydroxide solution (pH 9), dilutedwith water (80 ml) and extracted with ethyl acetate (3×100 mL). Thecombined organic fractions were washed with brine, dried (Na₂ SO₄) andthe solvent was evaporated under reduced pressure. The residue waspurified by flash column chromatography on silica gel, eluting withethyl acetate/hexane (75:25 increasing to 100:0). The first compound toelute was crystallized from ethyl acetate to give(+)-N-[(3R)-7-amino-2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-3-(2,4-dichlorophenyl)propanamide(413 mg, 57%) as a pale yellow solid, m.p. 179°-180° C., [α]_(D) +60.2°(c=0.500, CHCl₃).

δ_(H) (CDCl₃) 7.60 (2H, d, J 7 Hz), 7.49-7.36 (5H, m) 7.24 (1H, d, J 9Hz), 7.17 (2H, m), 6.99 (1H, dd, J 9, 3 Hz), 6.64 (1H, d, J 3 Hz), 5.54(1H, d, J 8 Hz), 4.80-3.50 (2H, br s), 3.39 (3H, s), 3.09 (2H, t, J 8Hz), and 2.68 (2H, dt, J_(d) 3, J_(t) 8 Hz). Anal. Calcd. for C₂₅ H₂₂Cl₂ N₄ O₂ : C, 62.38; H, 4.61; N, 11.64. Found: C, 62.58; H, 4.68; N,11.65%.

The second compound to elute was crystallized from ethyl acetate to give(+)-N-[(3R)-7-amino-2,3-dihydro-1-methyl-2-oxo-5-(2-aminophenyl)-1H-1,4-benzodiazepin-3-yl]-3-(2,4-dichlorophenyl)propanamide(114 mg, 15%) as a pale yellow solid, m.p. 188°-189° C., [α]_(D) +50.0°(c=0.100, MeOH).

δ_(H) (CDCl₃) 7.36 (2H, m), 7.25 (1H, d, J 9 Hz), 7.15 (3H, m), 7.00(1H, m), 6.88 (2H, m), 6.79 (1H, m), 6.60 (1H, bs), 5.52 (1H, d, J 8Hz), 4.10-2.80 (4H br s), 3.40 (3H, m), 3.09 (2H, t, J 8 Hz), and 2.69(2H, m). Anal. Calcd. for C₂₅ H₂₃ Cl₂ N₅ O₂.0.05EtOAc: C, 60.43; H,4.71; N, 13.99. Found: C, 60.79; H, 4.74; N, 13.83%.

EXAMPLE 76 ##STR179##(+)-N-[(3R)-2,3-Dihydro-1-methyl-2-oxo-5-phenyl-7-methanesulfonamido-1H-1,4-benzodiazepin-3-yl]-3-(2,4-dichlorophenyl)propanamide

Methanesulfonyl chloride (0.040 mL, 0.52 mmol) was added to a solutionof(+)-N-[(3R)-7-amino-2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-3-(2,4-dichlorophenyl)propanamide(193 mg, 0.40 mmol) and pyridine (0.065 mL, 0.80 mmol) in methylenechloride (1.6 mL). The resulting solution was stirred 2 h. The solutionwas diluted with ethyl acetate (12 mL), washed with 1N HCl, water,saturated sodium bicarbonate solution, water, and brine (3 mL each),dried (Na₂ SO₄) and the solvent was evaporated under reduced pressure.The residue was dissolved in warm toluene, treated with charcoal, andfiltered. The filtrate was diluted with hexane, the mixture was cooled,and the resulting precipitate was collected and dried in vacuo to give(+)-N-[(3R)-2,3-dihydro-1-methyl-2-oxo-5-phenyl-7-methanesulfonamido-1H-1,4-benzodiazepin-3-yl]-3-(2,4-dichlorophenyl)propanamide(152 mg, 68%) as a white solid, m.p. 130°-148° C., [α]_(D) +111.6°(c=0.500, CHCl₃).

δ_(H) (CDCl₃) 7.55-7.32 (9H, m), 7.24 (2H, dd, J 10, 2 Hz), 7.17 (1H,dd, J 9, 2 Hz), 7.05 (1H, d, J 3 Hz), 5.49 (1H, d, J 8 Hz), 3.41 (3H,s), 3.08 (2H, t, J 8 Hz), 2.97 (3H, s), and 2.71 (2H, dt, J_(d) 3, J_(t)8 Hz). Anal. Calcd. for C₂₆ H₂₄ Cl₂ N₄ O₄ S: C, 55.82; H, 4.32; N,10.01. Found: C, 56.12; H, 4.47; N, 9.89%.

EXAMPLE 77 ##STR180##N-(2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-pyrido[4,3-e]-1,4-diazepin-3-yl)-3-(2,4-dichlorophenyl)propanamidehydrochloride

Step A:

To a solution of2,3-dihydro-1-methyl-5-phenyl-1H-pyrido[4,3-e]-1,4-diazepine-2-one (J.Med. Chem. 1965, 8, 722-724) (1.63 g, 6.5 mmol) in toluene (32 mL) underargon cooled to -20° C. (ice/methanol bath) was added potassiumt-butoxide (1.83 g, 16.3 mmol). The resulting purple suspension wasstirred 15 min. at -20° C. and isoamyl nitrite (1.05 mL, 7.8 mmol) wasadded. The mixture was stirred at -20° C. for 30 min., then poured intoa mixture of water (50 mL), acetic acid (3 mL), and ethyl acetate (65mL). The mixture was stirred to dissolve all solids and the layers wereseparated. The aqueous layer was extracted with ethyl acetate (65 mL).The combined organic fractions were washed with saturated sodiumbicarbonate solution and brine (20 mL each), dried (Na₂ SO₄), and thesolvent was evaporated under reduced pressure. The residue wastriturated with cold toluene and the solid was collected and dried invacuo to give2,3-dihydro-3-hydroxyimino-1-methyl-5-phenyl-1H-pyrido[4,3-e]-1,4-diazepine-2-one(1.22 g, 67%) as a yellow solid, m.p. 223°-224° C.

δ_(H) (CDCl₃) 8.92 (1H, bs), 8.73 (1H, d, J 7 Hz), 8.62 (1H, s), 7.80(2H, dd, J 7, 1 Hz), 7.59 (1H, m), 7.48 (2H, m), 7.26 (1H, d, J 7 Hz),and 3.50 (3H,s).

Step B:

A mixture of2,3-dihydro-3-hydroxyimino-1-methyl-5-phenyl-1H-pyrido[4,3-e]-1,4-diazepine-2-one(1.77 g, 6.3 mmol) and freshly prepared Raney nickel (3.2 g) in 1:1ethanol/methanol (190 mL) was shaken on a Parr hydrogenation apparatusunder hydrogen (50 psi) for 4 h. The mixture was filtered through filteraid and the filtrate was evaporated under reduced pressure. The residuewas purified by flash column chromatography on silica gel, eluting withmethanol/chloroform/acetic acid (5:95:1 increasing to 10:90:1). Thematerial which eluted was stirred under chloroform (30 mL) withpotassium carbonate (0.3 g) and water (0.2 mL) for 5 min. The mixturewas dried (Na₂ SO₄) and the solvent was evaporated under reducedpressure to give3-amino-2,3-dihydro-1-methyl-5-phenyl-1H-pyrido[4,3-e]-1,4-diazepine-2-one(276 mg, 16%), as a yellow solid, m.p. 109°-123° C.

δ_(H) (CDCl₃) 8.72 (1H, d, J 6 Hz), 8.58 (1H, s), 7.61 (2H, m), 7.51(1H, m), 7.43 (2H, m), 7.26 (1H, m), 4.47 (1H, s), 3.50 (3H, s), and 2.1(2H, bs). High res. mass spectrum: Theoretical mass for C₁₅ H₁₄ N₄ O(M+1): 267.124586. Measured mass (M+1): 267.123654.

Step C:

A solution of dicyclohexylcarbodiimide (87 mg, 0.42 mmol) in methylenechloride (0.17 mL) was added to a solution of3-amino-2,3-dihydro-1-methyl-5-phenyl-1H-pyrido[4,3-e]-1,4-diazepine-2-one(93 mg, 0.35 mmol) and 3-(2,4-dichlorophenyl)propionic acid (83 mg, 0.38mmol) in tetrahydrofuran (0.5 mL) under argon. The resulting mixture wasstirred for 5 h., filtered, and the filtrate was evaporated underreduced pressure. The residue was purified by preparative platechromatography on silica gel eluting with methanol/chloroform/aceticacid (5:95:1). The purified material was stirred under chloroform (5 mL)with potassium carbonate (0.1 g) and water (2 drops) for 5 min. Themixture was dried (Na₂ SO₄) and the solvent was evaporated under reducedpressure. The residue was suspended in ethanol (2 mL) and ethanolic HCl(6.8M, 0.147 mL) was added. The mixture was stirred, the resultingprecipitate was collected and dried in vacuo to giveN-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-pyrido[4,3-e]-1,4-diazepin-3-yl)-3-(2,4-dichlorophenyl)propanamidehydrochloride (32 mg, 18%) as a white solid, m.p. 218°-219° C.

δ_(H) (d₆ -DMSO) 9.38 (1H, d, J 8 Hz), 8.86 (1H, bs), 8.59 (1H bs), 7.79(1H, d, J 6 Hz), 7.56 (3H, m), 7.51 (2H, m), 7.39 (2H, m), 7.25 (1H, m),7.16 (1H, m), 5.37 (1H, d, J 8 Hz), 3.44 (3H, s) 2.94 (2H, t, J 7 Hz),and 2.64 (2H, t, J 7 Hz). Anal. Calcd. for C₂₄ H₂₀ Cl₂ N₄ O₂.HCl: C,57.22; H, 4.20; N, 11.12. Found: C, 56.87; H. 4.18; N, 11.09%.

EXAMPLE 78 ##STR181##N-(2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-pyrido[4,3-e]-1,4-diazepin-3-yl)-3-(cyclohexyl)propanamide

A solution of dicyclohexylcarbodiimide (87 mg, 0.42 mmol) in methylenechloride (0.17 mL) was added to a solution of3-amino-2,3-dihydro-1-methyl-5-phenyl-1H-pyrido[4,3-e]-1,4-diazepine-2-one(93 mg, 0.35 mmol) and cyclohexanepropionic acid (0.065 mL, 0.38 mmol)in tetrahydrofuran (0.5 mL) under argon. The resulting mixture wasstirred for 5 h., filtered, and the filtrate was evaporated underreduced pressure. The residue was purified by preparative platechromatography on silica gel eluting with methanol/chloroform/aceticacid (5:95:1). The purified material was stirred under chloroform (5 mL)with potassium carbonate (0.1 g) and water (2 drops) for 5 min. Themixture was dried (Na₂ SO₄) and the solvent was evaporated under reducedpressure. The residue was crystallized from toluene to giveN-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-pyrido[4,3-e]-1,4-diazepin-3-yl)-3-(cyclohexyl)-propanamide(47 mg, 33%) as a white crystalline solid, m.p. 170° -173° C.

δ_(H) (CDCl₃) 8.75 (1H, d, J 6 Hz), 8.61 (1H, s), 7.58 (2H, m), 7.52(1H, m), 7.45 (2H, m), 7.31 (1H, d, J 6 Hz), 7.21 (1H, d, J 8 Hz), 5.54(1H, d, J 8 Hz), 3.51 (3H, s), 2.39 (2H, m), 1.73 (4H, m), 1.63 (3H, m),1.85-1.12 (4H, m), and 0.94 (2H, m). Anal. Calcd. for C₂₄ H₂₈ N₄O₂.0.10PhCH₃ : C, 71.70; H, 7.02; N, 13.54. Found: C, 71.78; H, 7.01; N,13.57%.

Employing the procedure substantially as described above, butsubstituting 3-(4-trifluoromethylphenyl)-propionic acid for thecyclohexanepropionic acid, the following compound was prepared:

EXAMPLE 79 ##STR182##N-(2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-pyrido[4,3-e]-1,4-diazepin-3-yl)-3-(4-trifluoromethylphenyl)propanamide

m.p. 191°-192° C. δ_(H) (CDCl₃) 8.76 (1H, d, J 6 Hz), 8.61 (1H, s), 7.56(4H, m), 7.52 (1H, m), 7.42 (2H, d, J 7 Hz), 7.38 (2H, m), 7.30 (1H, d,J 6 Hz), 7.22 (1H, d, J 8 Hz), 5.51 (1H, d, J 8 Hz), 3.50 (3H, s), 3.09(2H, t, J 8 Hz), and 2.73 (2H, t, J 8 Hz). Anal. Calcd. for C₂₅ H₂₁ F₃N₄ O₂.0.20PhCH₃ : C, 65.39; H, 4.70; N, 11.56. Found: C, 65.69; H, 4.64;N, 11.95%.

EXAMPLE 80 ##STR183##N-(2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-pyrido[3,4-e]-1,4-diazepin-3-yl)-3-(2,4-dichlorophenyl)propanamide

Step A:

To a solution of2,3-dihydro-1-methyl-5-phenyl-1H-pyrido[3,4-e]-1,4-diazepine-2-one (Can.J. Chem. 1987, 65, 1158-1161) (1.43 g, 5.7mmol) in toluene (28 mL) underargon cooled to -20° C. (ice/methanol bath) was added potassiumt-butoxide (1.59 g, 14.2 mmol). The resulting purple suspension wasstirred 15 min. at -20° C. and isoamyl nitrite (0.92 mL, 6.8 mmol) wasadded. The mixture was stirred at -20° C. for 30 min., then poured intoa mixture of water (25 mL), acetic acid (2.5 mL), and ethyl acetate (55mL). The mixture was stirred to dissolve all solids and the layers wereseparated. The aqueous layer was extracted with ethyl acetate (2×55 mL).The combined organic fractions were washed with saturated sodiumbicarbonate solution and brine (20 mL each), dried (Na₂ SO₄), and thesolvent was evaporated under reduced pressure. The residue wastriturated with hexane and the solid was collected and dried in vacuo togive2,3-dihydro-3-hydroxyimino-1-methyl-5-phenyl-1H-pyrido[3,4-e]-1,4-diazepine-2-one(1.60 g, 100%) as a tan foam.

δ_(H) (CDCl₃) 8.77 (1H, s), 8.50 (1H, d, J 4 Hz), 7.81 (2H, dd, J 8, 1Hz), 7.60 (1H, m), 7.49 (3H, m), 7.32 (1H, d, J 5 Hz), and 3.55 (3H,s).

Step B:

A solution of stannous chloride dihydrate (3.72 g, 16.5 mmol) inconcentrated hydrochloric acid (11 mL) was added dropwise to2,3-dihydro-3-hydroxyimino-1-methyl-5-phenyl-1H-pyrido[3,4-e]-1,4-diazepine-2-one(1.54 g, 5.5 mmol) cooled in an ice bath. The resulting solution wasstirred at ambient temperature for 3 h. The solution was diluted withwater (20 mL), basified with concentrated ammonium hydroxide (18 mL),and extracted with ether (4×75 mL). The combined organic fractions werewashed with brine (30 mL), dried (Na₂ SO₄), and the solvent wasevaporated under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel, eluting withmethanol/chloroform/acetic acid (5:95:1 increasing to 10:90:1). Thematerial which eluted was stirred under chloroform (20 mL) withpotassium carbonate (0.3 g) and water (2 drops) for 5 min. The mixturewas dried (Na₂ SO₄) and the solvent was evaporated under reducedpressure. The residue was stirred under hexane, and the resulting solidwas collected to give3-amino-2,3-dihydro-1-methyl-5-phenyl-1H-pyrido[3,4-e]-1,4-diazepine-2-one(241 mg, 16%) as a yellow solid, m.p. 94°-118° C.

δ_(H) (CDCl₃) 8.79 (1H, s), 8.48 (1H, d, J 5 Hz), 7.62 (2H, dd, J 8, 1Hz), 7.51 (1H, m), 7.45 (2H, m), 7.24 (1H, dd, J 5, I Hz), 4.47 (1H, s),3.55 (3H, s), and 2.2 (2H, bs). Anal. Calcd. for C₁₅ H₁₄ N₄ O.0.25(C₂H₅)₂ O: C, 67.46; H, 5.84; N, 19.67. Found: C, 67.28; H, 5.66; N,19.53%. High res. mass spectrum: Theoretical mass for C₁₅ H₁₄ N₄ O(M+1): 267.124586. Measured mass (M+1): 267.123093.

Step C:

A solution of oxalyl chloride (0.023 mL, 0.26 mmol) in methylenechloride (0.2 mL) was added dropwise to a solution of3-(2,4-dichlorophenyl)propionic acid (48 mg, 0.22 mmol) and DMF (1 drop)in methylene chloride (0.5 mL) cooled in an ice-bath. The resultingsolution was stirred 1 h. with cooling. The solvent was evaporated underreduced pressure to give 3-(2,4-dichlorophenyl)propionyl chloride (52mg, 100%). To a solution of3-amino-2,3-dihydro-1-methyl-5-phenyl-1H-pyrido[3,4-e]-1,4-diazepine-2-one(53 mg, 0.20 mmol) and pyridine (0.021 mL, 0.22 mmol) in methylenechloride (3 mL), was added a solution of 3-(2,4-dichlorophenyl)propionylchloride (52 mg, 0.22 mmol) in methylene chloride (0.5 mL). The mixturewas stirred for 1 h., the solvent was partially evaporated under reducedpressure, and the reaction mixture was purified by flash columnchromatography on silica gel, eluting with methanol/ether (5:95increasing to 7.5:92.5). The material which eluted was crystallized fromtoluene/hexane to giveN-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-pyrido[3,4-e]-1,4-diazepin-3-yl)-3-(2,4-dichlorophenyl)propanamide(38 mg, 38%) as a white crystalline solid, m.p. 220°-221° C.

δ_(H) (CDCl₃) 8.81 (1H, s), 8.52 (1H, d, J 5 Hz), 7.56 (2H, dd, J 7, 2Hz), 7.51 (1H, m), 7.44 (2H, d, J 6 Hz), 7.40 (1H, m), 7.27 (2H, m),7.18 (2H, dd, J 8, 2 Hz), 5.48 (1H, d, J 8 Hz), 3.55 (3H, s), 3.10 (2H,t, J 7 Hz), and 2.71 (2H, dt, J_(d) 2 J_(t) 8 Hz). Anal. Calcd. for C₂₄H₂₀ Cl₂ N₄ O₂.0.25PhCH₃ : C, 63.06; H, 4.52; N, 11.43. Found: C, 63.03;H, 4.48; N, 11.25%.

EXAMPLE 81N-[2,3-Dihydro-1-methyl-2-oxo-5-isopropyl-1H-1,4-benzodiazepin-3-yl]-3-(2,4-dichlorophenyl)propanamide

Step A: ##STR184##

To a solution of the benzodiazepine (1.0 g, 5.3 mmol) in THF (20 mL) at-78° C. under argon was added 60% (NaH, 2.52 g, 6.3 mmol) Boc anhydride(1.27 g, 5.8 mmol) and the mixture stirred at -78° C. for 1/2 hour. Thereaction was then allowed to warm to 25° C. and stirred for 2 hoursbefore quenching into cold aq. NH₄ Cl (10%) and extracting the productinto ethyl acetate (3×50 mL). Concentration of the dried (Na₂ SO₄)extracts gave an oil which was passed through silica (EtOAc/hexane) togive 1.35 g product (89%).

¹ H NMR (CDCl₃) δ: 1.60 (s, 9H), 3.40 (s, 3H), 3.95 (brd, 1H), 4.80(brd, 1H), 7.20 (d, 1H), 7.30 (q, 1H), 7.60 (t, 1H), 7.92 (d, 1H).

Step B: ##STR185##

To a solution of the BOC-benzodiazepine (4.0 g, 13.8 mmol) in THF (80mL) under argon was rapidly added a solution of isopropylmagnesiumchloride (2.0M) in THF (7.66 mL, 15.3 mmol). The reaction was stirredfor 1/2 hour, quenched into aq NH₄ Cl (50 mL), and extracted with ethylacetate (2×200 mL). The organic extracts were concentrated andchromatographed on silica (1:1, EtOAC/hexane) to give 1.55 g (34%) ofproduct.

¹ H NMR (CDCl₃) δ: 1.14 (d, 3H), 1.19 (d, 3H), 1.40 (s, 9H), 3.13 (s,3H), 3.2-3.8 (m, 3H), 5.45 (brs, 1H), 7.28 (dt, 1H), 7.48 (dt, 1H), 7.56(dt, 1H), 7.72 (dd, 1H).

Step C: ##STR186##

To a 0° C. solution of the isopropylphenone (1.55 g) in ethyl acetatewas added anhydrous HCl gas over 90 min. The reaction was thenconcentrated in vacuo to give a solid which was dissolved in H₂ O (40mL) and the pH adjusted to 11.0 with 1N LiOH. After 30 min. at pH=11.0the pH was adjusted to 7.0 with 1N HCl and product extracted into ethylacetate. The organic extracts were dried (Na₂ SO₄), filtered andconcentrated to give a solid 1.22 g, 100%.

¹ H NMR (CDCl₃) δ: 0.95 (d, 3H), 1.30 (d, 3H), 3.16 (septet, 1H), 3.36(s, 3H), 3.60 (d, 1H), 4.60 (d, 1H), 7.2-7.3 (m, 2H), 7.45-7.55 (m, 2H).

Step D:

The benzodiazepine obtained in Step C was converted to the oxime asdescribed in Example 80 Step A.

Step E:

The oxime (2 gms) was dissolved in acetic acid (150 mL) and 10% Pd/C (1gm) added. The mixture was stirred rapidly under an atmosphere ofhydrogen for 90 min or until complete by HPLC. The reaction wasfiltered, the catalyst washed with methylene chloride (200 mL) and thefiltrates concentrated in vacuo to an oil. The oil was dissolved insaturated aqueous sodium bicarbonate (100 mL) and product extracted withethyl acetate (3×150 mLs). Concentration of the dried (Na₂ SO₄) extractsgave 2.60 gms (97%).

Step F:

The anine was coupled with 3-(2,4-dichlorophenyl)propionic acid asdescribed in Example 43 to yieldN-(2,3-dihydro-1-methyl-2-oxo-5-isopropyl-1H-1,4-benzodiazepin-3-yl)-3-(2,4-dichlorophenyl)propanamide.

¹ H NMR (CDCl₃) δ: 0.92 (d, 3H), 1.25 (d, 3H), 2.65 (dt, 2H), 3.05 (t,2H), 3.15 (SepT, 1H), 3.40 (s, 3H), 5.38 (d, 1H), 7.0-7.6 (m, 8H).

The following compounds were prepared in a similar manner as describedin Example 81, using the appropriate Grignard reagent in place ofisopropyl magnesium chloride.

EXAMPLE 82N-[2,3-dihydro-1-methyl-2-oxo-5-isopropyl-1H-1,4-benzodiazepin-3-yl]-3-cyclohexylpropanamide

m.p. 164°-165° C. CHN: Anal. Calcd. for C₂₂ H₃₁ N₃ O₂ : C, 71.51; H,8.46; N, 11.37 Observed: C, 71.72; H, 8.39; N, 11.32

EXAMPLE 83N-[2,3-dihydro-1-methyl-2-oxo-5-isopropyl-1H-1,4-benzodiazepin-3-yl]-3-(4-trifluoromethylphenyl)propanamide

m.p. 187°-188° C. ¹ H NMR (CDCl₃) δ: 0.92 (d, 3H), 1.25 (d, 3H), 2.66(dt, 2H), 3.04 (t, 2H), 3,15 (SepT, 1H), 3.40 (S, 3H), 5.38 (d, 1H),7.14 (brd, 1H), 7.25-7.6 (m, 8H).

Employing substantially the same methods described in Example 80, butreplacing Step E with the reduction method described below, thefollowing compounds were prepared: ##STR187##

To a solution of the oxime 1 (1.28 g, 0.0048 mole) in H₂ O (130 ml) andTHF (65 ml) was added sodium dithionite (Na₂ S₂ O₄) (13.0 g, 0.075mole). The mixture was stirred for 2 hours then diluted with saturatedaqueous sodium bicarbonate (50 ml) and product extracted into ethylacetate (2×150 ml). The organic extracts were combined, dried over Na₂SO₄, filtered, and concentrated to give an oil (≈1.0 g). The oil waschromatographed on silica using ethyl acetate followed by 10%methanol/methylene chloride to give pure amine 0.778 g (64%).

¹ H NMR (DMSO) δ3.32 (s, 3H), 4.30 (s, 1H), 6.64 (d, d, 1H), 6.76 (d,1H), 7.35 (dt, 1H), 7.58-7.74 (m, 3H), 7.88 (m, 1H).

EXAMPLE 84N-[2,3-dihydro-1-methyl-2-oxo-5-(2-furanyl)-1H-1,4-benzodiazepin-3-yl]-3-cyclohexylpropanamide

m.p. 168°-169° C. CHN: Anal. Calcd. for C₂₃ H₂₇ N₃ O₃ : C, 70.21;H,6.92; N, 10.68 Observed: C, 70.15; H, 6.67; N, 10.64

EXAMPLE 85N-[2,3-dihydro-1-methyl-2-oxo-5-(2-furanyl)-1H-1,4-benxodiazepin-3-yl]-3-(4-trifluoromethylphenyl)propanamide

m.p. 155°-157° C. CHN: Anal. Calcd. for C₂₄ H₂₀ N₃ O₃ F₃ : C, 63.29; H,4.432; N, 9.23 Observed: C, 63.22; H, 4.44; N, 9.07

EXAMPLE 86N-[2,3-dihydro-1-methyl-2-oxo-5-(2-furanyl)-1H-1,4-benzodiazepin-3-yl]-3-(2,4-dichlrophenyl)propanamide

m.p. 132°-133° C. CHN: Anal. Calcd. for C₂₃ H₁₉ N₃ O₃ Cl₂ C, 60.54; H,4.20; N, 9.21 Found: C, 60.62; H, 4.07; N, 9.07

EXAMPLE 87N-[2,3-dihydro-1-methyl-2-oxo-5-(3-furanyl)-1H-1,4-benzodiazepin-3-yl]-3-cyclohexylpropanamide

m.p. 199°-200° C. ¹ H NMR (CDCl₃) δ: 0.9-1.8 (brm, 3H), 2.38 (t, 2H),3.42 (S, 3H), 5.55 (brd, 1H), 6.90 (S, 1H), 7.2-7.77 (m, 7H)

EXAMPLE 88N-[2,3-Dihydro-1-methyl-2-oxo-5-(3-furanyl)-1H-1,4-benzodiazepin-3-yl]-3-(4-trifluoromethylphenyl)propanamide

m.p. 213°-214° C. ¹ H NMR (CDCl₃) δ: 2.71 (dt, 2H), 3.05 (t, 2H), 3.42(S, 3H), 5.72 (d, 1H), 6.82 (brS, 1H), 7.2-7.7 (m, 11H)

EXAMPLE 89N-[2,3-Dihydro-1-methyl-2-oxo-5-[2'-(4,4-dimethyl-2-oxazolinyl)phenyl]-1H-1,4-benzodiazepin-3-yl]-3-(2,4-dichlorophenyl)propanamide

The subject compound was prepared substantially as described in Example81.

m.p. 194°-195° C. CHN: Anal. Calcd. for C₃₀ H₂₈ N₄ O₃ Cl₂ C, 63.95; H,5.01; N, 9.94 Found: C, 63.70; H, 5.01; N, 9.96

EXAMPLE 90N-[2,3,4,5-Tetrahydro-1-methyl-2-oxo-5-isopropyl-1H-1,4-benzodiazepin-3yl]-3-cyclohexylpropanamide##STR188##

A solution ofN-[2,3-dihydro-1-methyl-2-oxo-5-isopropyl-1H-1,4-benzodiazepin-3-yl]-3-cyclohexylpropanamide(50 mg) in methanol (10 mL), containing 10% Pd/C (50 mg) was stirredunder 1 atmosphere of hydrogen for 18 hours. Filtration of the reaction,concentration and crystallization from diethyl ether gave 21 mgN-[2,3,4,5-tetrahydro-1-methyl-2-oxo-5-isopropyl-1H-1,4-benzodiazepin-3-yl]-3-cyclohexylpropanamide.

CHN: Anal. Calcd. for C₂₂ H₃₃ N₃ O₂ C, 71.12; H, 8.95; N, 11.31Observed: C, 70.98; H, 8.97; N, 11.15 m.p. 114°-115° C.

EXAMPLE 91N-[2,3-dihydro-1-methyl-2-oxo-5-methyl-1H-1,4-benzodiazepin-3-yl]-3-(2,4-dichlorophenyl)propanamide

Step A: ##STR189##

To CBZ-benzodiazepine (250 mg, 0.776 mmol) in toluene (25 mL) at refluxwas added dropwise a solution of DMF dimethylacetal (1.09 mL) in toluene(10 mL). The reaction was refluxed for 5 hours, cooled and concentratedto an oil. The oil was triturated with ether to give a white solid (124mg).

¹ H NMR (CDCl₃) δ: 2.50 (s, 3H), 3.42 (s, 3H), 5.12-5.20 (m, 3H), 6.62(d, 1H), 7.25-6.4 (m, 7H), 7.5-7.6 (m, 2H).

Step B: ##STR190##

The CBZ-amine-N-methyl amide (190 mg) was treated with 30% HBr/AcOH (0.8mL) for 1 hour at room temperature. The reaction mixture was poured intoether (10 mL) at 0° C. and the solid filtered. Solid dissolved in 10%Aq. NaOH (5 mL) and CH₂ Cl₂ (10 mL) and organic layer separated, dried(Na₂ SO₄), filtered and concentrated to an oil (172 mg, 110%).

¹ H NMR (CDCl₃) δ: 2.42 (s, 3H), 3.05 (brs, 2H), 3.40 (s, 3H), 4.40 (s,1H), 7.2-7.6 (m, 4H).

Step C: ##STR191##

N-[2,3-dihydro-1-methyl-2-oxo-5-methyl-1H-1,4-benzodiazepin-3-yl]-3-(2,4-dichlorophenyl)propanamidewas prepared in a similar manner as described previously in Example 43.

m.p. 194°-195° C. CHN: Anal. Calcd. for C₂₀ H₁₉ N₃ O₂ Cl₂ C, 59.42; H,4.74; N, 10.39 Observed: C, 59.50; H, 4.74; N, 10.44 ¹ H NMR (CDCl₃) δ:2.49 (brs, 3H), 2.65 (dt, 2H), 3.05 (t, 2H), 3.42 (s, 3H), 5.35 (d, 1H),71-7.6 (m, 8H).

EXAMPLE 92N-[2,3-Dihydro-1-methyl-2-oxo-[4,5-a]-(1-oxo-1,3-dihydro-2H-isoindole)-1H-1,4-benzodiazepin-3-yl]-3-(2,4-dichlorophenyl)propanamide##STR192##

To a solution ofN-[2,3-dihydro-1-methyl-2-oxo-5-[2'-(4,4-dimethyl-2-oxazolinyl)phenyl]-1H-1,4-benzodiazepin-3-yl]-3-(2,4-dichlorophenyl)propanamide(100 mg, 0.178 mmol) in methylene chloride was slowly added methyltrifluoromethanesulfonate (22 mL, 0.198 mmol). After stirring 5 minutes,sodium borohydride (7.6 mg, 0.20 mmol) in asolute ethanol (0.5 mL) wasadded and reaction stirred 30 min. the product was extracted into ethylacetate and purified by column chromatography on silica (60% ethylacetate/hexane) to give 30 mgN-[2,3-dihydro-1-methyl-2-oxo-[4,5-a]-(1-oxo-1,3-dihydro-2H-isoindole)-1H-1,4-benzodiazepin-3-yl]-3-(2,4-dichlorophenyl)propanamide.

¹ H NMR (CDCl₃) δ: 2.70 (m, 2H), 3.12 (t, 2H), 3.55 (s, 3H), 5.68 (s,1H), 5.90 (d, 1H), 6.85 (dd, 1H), 7.05 (brd, 1H), 7.1-7.5 (m, 9H), 7.85(d, 1H). MS M⁺¹ -494.

EXAMPLE 93 ##STR193##3R-(+)-3-(Phenylthio)-N-[2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]propanamide

To a stirred solution of 3-bromopropionic acid (1.0 g, 6.5 mmol) in DMF(20 mL) was added K₂ CO₃ (1.8 g, 13 mmol) and thiophenol (0.72 g, 6.5mmol). This was heated to 50° C. for 1 h. The mixture was then dilutedwith 200 mL H₂ O and extracted with 2×100 mL EtOAc. The combinedorganics were washed with 100 mL H₂ O and dried with Na₂ SO₄. This wasevaporated to give 1.52 g of a colorless oil, 1.18 g corrected forresidual DMF by NMR.

The above oil was taken up in 30 mL DMF and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.45 g,12.8 mmol) and 1-hydroxybenztriazole hydrate (1.73 g, 12.8 mmol) wereadded. This was stirred for 5 min at rt.3-(R)-Amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one(0.66 g, 2.6mmol) was then added and the reaction was stirred at rtovernight. The reaction was diluted with 200 mL H₂ O and extracted with2×150mL EtOAc. The combined organics were washed with 1×100 mL H₂ O,dried with Na₂ SO₄ and evaporated. The residue was chromatographed oversilica eluting with 2% MeOH:CHCl₃. Collected pure fractions, evaporated.Evaporated from diethyl ether to give 770 mg of a white foam.

Anal. Calcd for C₂₅ H₂₃ N₃ O₂ S.0.05Hexane: C, 70.04; H, 5.51; N, 9.69.Found: C 69.91, H₅.40, N 9.78

EXAMPLE 94 ##STR194##3R-(+)-5-(Methylthio)-N-[2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]propanamide

To an aqueous solution of K₂ CO₃ (0.76 g, 5.5 mmol) was added5-bromopentanoic acid and sodium thiomethoxide. This was stirred at rtovernight. The reaction was diluted with 50 mL H₂ O and acidified topH=0 with 6N HCl. Extracted with 2×50 mL EtOAc. Dried with Na₂ SO₄,evaporated to give 0.55 g of a yellow oil.

The above oil was taken up in 10 mL DMF and1-(3-dimethyl-aminopropyl)-3-ethylcarbodiimide hydrochloride (1.30 g,6.8 mmol) and 1-hydroxybenztriazole hydrate (0.92 g, 6.8 mmol) wereadded.3-(R)-Amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodaizepin-2-one(0.85 g, 3.4 mmol) was then added and the reaction was stirred overnightat rt. The reaction was diluted with 100 mL H₂ O and extracted with 2×50mL EtOAc. Combined organics were dried with brine and Na₂ SO₄, andevaporated to give yellow oil. The residue was chromatographed oversilica eluting with 50:50 EtOAc:Hex to 100% EtOAc. Pure fractions werecollected to give 1.33 g of a colorless oil, 0.4 g of which waschromatographed over silica eluting with 2% MeOH:CH₂ Cl₂. Pure fractionswere collected, and evaporated from ethyl ether:hexane to give a whitepowder mp. 61°-65° C.

Anal. Calcd for C₂₂ H₂₅ N₃ O₂ S.0.35H₂ O: C, 65.76; H, 6.45; N, 10.46.Found: C, 65.81; H, 6.21; N, 10.57.

EXAMPLE 95 ##STR195##N-cyano-N'-cyclohexylmethyl-N"-(1,3-dihydro-1-methyl-2-oxo-5-phenyl-2H-1,4-benzodiazepin-3-yl)guanidine

A solution of3-(R)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one (1g, 3.7 mmole) in acetonitrile (20 mL) was treated withdiphenylcyanocarbonimidate (0.9 g, 3.7 mmole) and stirred at roomtemperature for thirty minutes. Cyclohexylmethylamine (0.84 g, 7.4mmole) was then added and the reaction stirred at room temperature fortwo hours. The reaction was poured into 100 mL of 0.1N HCl and extractedwith 3×100 mL portions of ethyl acetate. The organic layers werecombined and washed once with saturated sodium bicarbonate (50 mL),dried over anhydrous magnesium sulfate, filtered, and concentrated atreduced pressure. The residue was chromatographed on silica gel elutingwith 50% ethyl acetate/hexane to give 0.875 g of the product. Theanalytical sample was crystallized from ethyl acetate.

m.p. 158°-161° C. Anal. Calcd. for C₂₅ H₂₈ N₆ O: C, 70.07; H, 6.59; N,19.61. Found: C, 70.05; H, 6.59; N, 19.64%.

EXAMPLE 96 ##STR196##N-(1,3-Dihydro-1-methyl-2-oxo-5-phenyl-2H-1,4-benzodiazepin-3-yl)-4-(4-chlorobenzyl)-4-piperidinecarboxamidedihydrochloride

Step A:

Preparation ofN-tert-butyloxycarbonyl-4-(4-chlorobenzyl)-4-piperidinecarboxylic acid

A solution of N-Boc-ethylisonipecotate (51.4 g, 200 mmole) in THF (1 L)at -60° C. was treated with a solution of lithium bistrimethylsilylamide (220 mL of a 1N solution in THF, 220 mmole). After stirring at-60° C. for 5 minutes, a solution of 4-chlorobenzyl chloride (33.8 g,210 mmole) in THF (200 mL) was added and the reaction allowed to warm toroom temperature. Most of the THF (about 800 mL) was removed byevaporation at reduced pressure. The remainder was poured into 1 L of 1NHCl and extracted with two 800 mL portions of ethyl acetate. The organiclayers were combined and washed once with saturated sodium bicarbonate(500 mL), dried over anhydrous magnesium sulfate, filtered, andconcentrated at reduced pressure. The residue was chromatographed onsilica gel eluting with 10%-20% ethyl acetate/hexane to give the productester which was used directly. The material thus obtained was dissolvedin THF (100 mL) and IPA (100 mL) and treated with 350 mL of 10N NaOH.The mixture was heated to reflux for 30 hours. The reaction was cooledto room temperature and poured over a mixture of crushed ice (2 L), 6NHCl (500 mL) and saturated potassium hydrogen sulfate (1 L). The mixturewas extracted with two 1 L portions of ethyl acetate. The organic layerswere combined and dried over anhydrous magnesium sulfate, filtered, andconcentrated at reduced pressure to give 52 g of the product.

m.p. 179°-180° C., ¹ H NMR CDCl₃ δ7.26 (d, J=8 Hz, 2H), 7.03 (d, J=8 Hz,2H), 3.98 (m, 2H), 3.0-2.8 (m, 2H), 2.84 (s, 2H), 2.10-2.00 (m, 2H),1.55-1.40 (m, 2H), 1.45 (s, 9H)

Step B:

Preparation ofN-(1,3-dihydro-1-methyl-2-oxo-5-phenyl-2H-1,4-benzodiazepin-3-yl)-4-(4-chlorobenzyl)-4-piperidinecarboxamidedihydrochloride

A mixture consisting ofN-tert-butyloxycarbonyl-4-(4-chlorobenzyl)-4-piperidinecarboxylic acid(1.48 g, 4.18 mmole),3-(R)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one (1g, 3.7 mmole), hydroxybenzotriazole (1.17 g, 8.66 mmole),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.49 g,7.70 mmole), diisopropylethyl amine (0.53 g, 4.13 mmole), and DMF (10mL) was stirred at room temperature for 18 hours. The reaction waspoured into 1N HCl and extracted with ethyl acetate (4×50 mL). Theorganic layers were combined and washed once with saturated sodiumbicarbonate (50 mL), once with saturated sodium chloride (50 mL), driedover anhydrous magnesium sulfate, filtered, and concentrated at reducedpressure. The residue was chromatographed on silica gel eluting with25%-50% ethyl acetate/hexane to give 2.34 g of the product amide whichwas used directly. The material thus obtained was dissolved in ethylacetate (50 mL) and HCl (g) was bubbled into the reaction for 5 minutes.The reaction was concentrated at reduced pressure and the residuerecrystallized from ethyl acetate to give 1.13 g of the product as apale yellow solid.

m.p. 190°-195° C. Anal. Calcd. for C₂₉ H₂₉ ClN₄ O₂.2 HCl: C, 60.68; H,5.44; N, 9.76. Found: C, 60.47; H, 5.5; N, 9.42%.

Utilizing the procedures substantially as described above exceptsubstituting N-Boc-ethylnipecotate for N-Boc-ethyl isonipecotate therewere obtained the following compounds

EXAMPLE 97 ##STR197##N-(1,3-dihydro-1-methyl-2-oxo-5-phenyl-2H-1,4-benzodiazepin-3-yl)-3-(4-chlorobenzyl)-3-piperidinecarboxamidehydrochloride A+B isomers

Isomer A m.p. 205°-210° C. Anal. Calcd. for C₂₉ H₂₈ ClN₄ O₂.HCl.0.5 CH₃CH₂ OH.0.8 H₂ O: C, 62.67; H, 6.07; N, 9.75. Found: C, 62.69; H, 5.94;N, 9.42%.

Isomer B m.p. 200°-205° C. Anal. Calcd. for C₂₉ H₂₈ ClN₄ O₂.HCl.0.1 CH₃CH₂ OCOCH₃.1.6 H₂ O: C, 61.39; H, 5.96; N, 9.74. Found: C, 61.39; H,5.66; N, 9.56%.

EXAMPLE 98 ##STR198##(+)-3-Cyclohexyl-N-[2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-N-(ethoxycarbonylmethyl)propanamide

3-(R)-Amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one(5.0 g, 18.8 mmol) in acetonitrile (100 mL) was mixed with ethylbromoacetate (2.1 mL, 18.8 mmol) and sodium hydrogen carbonate (4.0 g)was suspended in the mixture. The mixture was stirred and heated atreflux for 2 h. After that time, the reaction was cooled to roomtemperature, diluted with 150 mL water, and extracted with ethyl acetate(3×100 mL). The organic layers were combined, dried with magnesiumsulfate, gravity filtered, and the solvent was removed in vacuo. Theresulting oil was chromatographed over silica in 3:1 ethylacetate:hexane, yielding the mono-alkylated product (2.58 g, 39%) aswell as the starting 1,4-benzodiazepin-2-one and bis-alkylated material.To a solution of 3-cyclohexylpropionic acid (1.0 g, 6.40 mmol) inmethylene chloride (30 mL) was added oxalyl chloride (0.56 mL, 6.40mmol) and catalytic (N,N)-dimethyl formamide (2 drops). After 0.5 h, asolution of the acetate (2.25 g, 6.40 mmol) in methylene chloride (10mL) was added and the reaction was stirred for 0.25 h. The reaction wasthen diluted with methylene chloride (150 mL) and saturated aqueoussodium hydrogen carbonate (150 mL) was added. The aqueous portion wasextracted again with methylene chloride (2×100 mL) and the organics werecombined, dried with magnesium sulfate, gravity filtered, and thesolvent was removed in vacuo. The resulting oil was chromatographed oversilica with 1:1 ethyl acetate:hexane, yielding a foam that wascrystallized with ether, giving 2.0 g (64%) of the product.

m.p. 120°-122° C., [α]_(d) +0.63° (c=0.79; MeOH). Anal. Calcd. for C₂₉H₃₅ N₃ O₄ : C, 71.14; H, 7.21; N, 8.58. Found: C, 71.13; H, 7.13; N,8.75%.

The following compound was prepared in a manner substantially asdescribed above except substituting ethyl bromobutyrate for ethylbromoacetate.

EXAMPLE 99 ##STR199##3-Cyclohexyl-N-[2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-N-(ethoxycarbonylpropyl)propanamide

m.p. 103°-105° C., [α]_(d) 0.00°; c=0.85; MeOH. Anal. Calcd. for C₃₁ H₃₉N₃ O₄.0.40 mol H₂ O: C, 70.94; H, 7.64; N, 8.01. Found: C, 70.91; H,7.44; N, 8.12%.

EXAMPLE 100 ##STR200##N-[2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-N-[2-(2-methoxyethoxy)ethyl]hexanamide

3-(R)-Amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one(1.33 g, 5.0 mmol) in N,N-dimethyl formamide (30 mL) was mixed with1-bromo-2-(2-methoxyethoxy)ethane (1.35 mL, 5.0 mmol) and triethylamine(1.0 mL). The mixture was stirred and heated at reflux for 4 h. Afterthat time, the reaction was cooled to room temperature, diluted with 150mL water, and extracted with ethyl acetate (3×100 mL). The organiclayers were combined, dried with magnesium sulfate, gravity filtered,and the solvent was removed in vacuo. The resulting oil waschromatographed over silica in 1:1 ethyl acetate:hexane, yielding themono-alkylated product (1.2 g, 65%) as well as the starting1,4-benzodiazepin-2-one and bis-alkylated material. To a solution of themono-alkylated material (1.2 g, 3.27 mmol) in methylene chloride (20 mL)was added hexanoyl chloride (0.96 mL, 3.27 mmol) and the reaction wasstirred for 0.25 h. The reaction was then diluted with methylenechloride (150 mL) and saturated aqueous sodium hydrogen carbonate (150mL) was added. The aqueous portion was extracted again with methylenechloride (2×100 mL) and the organics were combined, dried with magnesiumsulfate, gravity filtered, and the solvent was removed in vacuo. Theresulting oil was chromatographed over silica with 1:1 ethylacetate:hexane, yielding an oil, giving 580 mg (38%) of the product.

[α]_(d) 0.00°; c=0.27; MeOH. Anal. Calcd. for C₂₇ H₃₅ N₃ O₄.0.80 mol H₂O: C, 67.56; H, 7.69; N, 8.75. Found: C, 67.56; H, 7.39; N, 8.85%.

EXAMPLE 101 ##STR201##(+)-N-[2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-N-(5-hydroxypentyl)hexanamide

3-(R)-Amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one(1.33 g, 5.0 mmol) in acetonitrile (40 mL) was mixed with5-chloropentan-1-ol (0.61 g, 5.0 mmol) and sodium hydrogen carbonate(2.0 g) was suspended in the mixture. The mixture was stirred and heatedat reflux for 12 h. After that time, the reaction was cooled to roomtemperature, diluted with 100 mL water, and extracted with ethyl acetate(3×75 mL). The organic layers were combined, dried with magnesiumsulfate, gravity filtered, and the solvent was removed in vacuo. Theresulting oil was chromatographed over silica in 1:49methanol:chloroform yielding the mono-alkylated product (1.1 g, 62%) aswell as the starting 1,4-benzodiazepin-2-one and bis-alkylated material.To a solution of the monoalkylated material (0.50 g, 1.42 mmol) inmethylene chloride (30 mL) was added hexanoyl chloride (0.20 mL, 1.42mmol) and the reaction was stirred for 0.25 h. The reaction was thendiluted with methylene chloride (100 mL) and saturated aqueous sodiumhydrogen carbonate (100 mL) was added. The aqueous portion was extractedwith methylene chloride (2×75 mL) and the organics were combined, driedwith magnesium sulfate, gravity filtered, and the solvent was removed invacuo. The resulting oil was chromatographed over silica with 1:1 ethylacetate:hexane, yielding a foam, giving 360 mg (64%) of the product.

foam, [α]_(d) +8.36° (c=0.61, MeOH). Anal. Calcd. for C₂₇ H₃₅ N₃ O₂.0.25mol H₂ O: C, 71.42; H, 7.88; N, 9.25. Found: C, 71.47; H, 7.89; N,9.12%.

EXAMPLE 102 ##STR202##(+)-N-[2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-N-(ethoxycarbonylpentyl)hexanamide

3-(R)-Amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one(1.33 g, 5.0 mmol) in acetonitrile (40 mL) was mixed withethyl-6-bromohexanoate (0.89 mL, 5.0 mmol) and sodium hydrogen carbonate(2.0 g) was suspended in the mixture. The mixture was stirred and heatedat reflux for 10 h. After that time, the reaction was cooled to roomtemperature, diluted with 100 mL water, and extracted with ethyl acetate(3×75 mL). The organic layers were combined, dried with magnesiumsulfate, gravity filtered, and the solvent was removed in vacuo. Theresulting oil was chromatographed in 1:49 methanol:chloroform, yieldingthe mono-alkylated product (0.56 g, 28%) as well as the starting1,4-benzodiazepin-2-one and bis-alkylated material. To a solution of themono-alkylated material (0.56 g, 1.37 mmol) in methylene chloride (20mL) was added hexanoyl chloride (0.19 mL, 1.37 mmol) and the reactionwas stirred for 0.25 h. The reaction was then diluted with methylenechloride (100 mL) and saturated aqueous sodium hydrogen carbonate (100mL) was added. The aqueous portion was extracted again with methylenechloride (2×75 mL) and the organics were combined, dried with magnesiumsulfate, gravity filtered, and the solvent was removed in vacuo. Theresulting oil was chromatographed over silica with 1:1 ethylacetate:hexane, yielding a foam, giving 0.40 g (58%) of the product.

m.p. 59°-65° C., [α]_(d) (+)52.7° (c=0.48,MeOH). Anal. Calcd. for C₃₀H₃₉ N₃ O₄.0.20 mol CH₂ Cl₂ : C, 69.4; H, 7.6; N, 8.04. Found: C, 69.44;H, 7.68; N, 7.71%.

The following compound was prepared in a manner substantially asdescribed above except substituting ethyl bromoacetate for ethyl6-bromohexanoate.

EXAMPLE 103 ##STR203##(+)-N-[2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-N-(ethoxycarbonylmethyl)hexanamide

foam, [α]_(d) +2.04° (c=0.98; MeOH). Anal. Calcd. for C₂₆ H₃₁ N₃ O₄ : C,69.47; H, 6.95; N, 9.35. Found: C, 69.41; H, 7.03; N, 9.26%.

EXAMPLE 104 ##STR204##(+)-3-Cyclohexyl-N-[2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-N-(hydroxymethyl)propanamide

(+)-3-Cyclohexyl-N-[2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]propanamide(2.0 g, 5.0 mmol) was dissolved in tetrahydrofuran (30 mL), cooled to 0°C. and methyl magnesium chloride (3M, 2.0 mL) was added. After 0.25 h,paraformadehyde (0.15 g, 10 mmol) was added, and the mixture was allowedto warm to room temperature. The reaction was then diluted with ethylacetate (150 mL) and saturated aqueous sodium hydrogen carbonate (150mL) was added. The aqueous portion was extracted again with ethylacetate (2×100 mL) and the organics were combined, dried with magnesiumsulfate, gravity filtered, and the solvent was removed in vacuo. Theresulting oil was chromatographed over silica with 1:1 ethylacetate:hexane, yielding a foam (0.80 g, 37%).

foam, [α]_(d) +124° (c=0.69, MeOH). Anal. Calcd. for C₂₆ H₃₁ N₃ O₃ : C,72.03; H, 7.21; N, 9.69. Found: C, 71.66; H, 7.08; N, 9.78%.

The following compound was prepared in a manner substantially asdescribed above starting from(+)-N-[2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]hexanamide.

EXAMPLE 105 ##STR205##(+)-N-[2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-N-(hydroxymethyl)hexanamide

m.p. 154°-156° C., [α]_(d) +190.8° (c=0.24, MeOH). Anal. Calcd. for C₂₃H₂₇ N₃ O₃.0.30 mol H₂ O: C, 69.26; H, 6.97; N, 10.53. Found: C, 69.29;H, 6.81; N, 10.6%.

EXAMPLE 106 ##STR206##(+)-3-Cyclohexyl-N-[2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-N-(tetrazolylmethyl)propanamide

(+)-3-Cyclohexyl-N-[2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-N-(hydroxymethyl)propanamide(0.67 g, 1.56 mmol) was dissolved in methylene chloride(100 mL), alongwith tetrazole (0.33 g, 4.7 mmol), and thenN,N-diisopropyldibenzyl-phosphoramidite (1.07 g, 3.1 mmol). After 2 h,the mixture was diluted with methylene choride (150 mL), and extractedwith saturated aqueous sodium hydrogen carbonate (3×100 mL). The organiclayers were combined, dried with magnesium sulfate, gravity filtered,and the solvent was removed in vacuo. The resulting oil waschromatographed twice over silica with 1:1 ethyl acetate:hexane,yielding two constitutional isomers, a (65 mg, 9%) and b (56 mg, 7.5%).

Isomer A: m.p. 96°-98° C., [α]_(d) +188.9° (c=0.19, MeOH). Anal. Calcd.for C₂₇ H_(3l) N₇ O₂.0.30 mol TFA: C, 63.78; H, 6.07; N, 18.86. Found:C, 63.7; H, 6.12; N, 18.76%.

Isomer B: m.p. 92°-95° C., [α]_(d) +81.3° (c=0.31, MeOH). Anal. Calcd.for C₂₇ H₃₁ N₇ O₂ 0.35 mol TFA: C, 63.31; H, 6.01; N, 18.66. Found: C,63.35; H, 6.02; N, 18.74%.

EXAMPLE 107 ##STR207##3R-(+)-3-(Benzyloxycarbonylamino)-2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepine

To a stirring solution of3-(R)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one(2.0 g, 7.5 mmol) in methylene chloride (45 mL) at 0° C. was addedbenzyl chloroformate (1.2 mL, 8.3 mmol) and the reaction was allowed towarm to room temperature. The reaction mixture was diluted withmethylene chloride (150 mL), and extracted with saturated aqueous sodiumhydrogen carbonate (150 mL). The aqueous portion was extracted withmethylene chloride (2×100 mL) and the organics were combined, dried withmagnesium sulfate, gravity filtered, and the solvent was removed invacuo. The resulting oil was chromatographed over silica with 1:1 ethylacetate:hexane, yielding a white foam (3.0 g, 99.7%) [α]_(d) +57.5°(c=1.17; MeOH).

Anal. Calcd. for C₂₄ H₂₀ N₃ O₃.0.70 mol H₂ O.0.15 mol CHCl₃ : C, 67.62;H, 5.06; N, 9.8. Found: C, 67.6; H, 5.02; N, 9.75%.

The following compounds were prepared substantially as described inExample 81.

EXAMPLE 108N-[2,3-Dihydro-1-methyl-2-oxo-5-ethyl-1H-1,4-benzodiazepin-3-yl]-3-(2,4-dichlorophenyl)propanamide

m.p. 156°-158° C. CHN: Anal. Calcd. for C₂₁ H₂₁ Cl₂ N₃ O₂.0.5 H₂ O: C,59.02; H, 5.19; N, 9.83. Found: C, 58.99; H, 4.89; N, 9.88.

EXAMPLE 109N-[2,3-Dihydro-1-methyl-2-oxo-5-t-butyl-1H-1,4-benzodiazepin-3-yl]-3-(2,4-dichlorophenyl)propanimide

m.p. 170°-171° C. CHN: Anal. Calcd. for C₂₃ H₂₅ Cl₂ N₃ O₂.0.7 H₂ O: C,60.18; H, 5.80; N, 9.16. Found: C, 60.17; H, 5.30; N, 9.30.

EXAMPLE 110N-[2,3-Dihydro-1-methyl-2-oxo[4'-(4,4-dimethyl-2-oxazolinyl)phenyl]-1H-1,4-benzodiazepin-3-yl]-3-(2,4-dichlorophenyl)propanamide

m.p. 188°-190° C. CHN: Anal. Calcd. for C₃₀ H₂₈ N₄ O₃ Cl₂ : C, 63.95; H,5.01; N, 9.94. Found: C, 63.96; H, 5.02; N, 10.08.

EXAMPLE 111N-[2,3-Dihydro-1-methyl-2-oxo-5-(4-methoxyphenyl)-1H-1,4-benzodiazepin-3-yl]-3-(2,4-dichlorophenyl)propanamide

m.p. 188°-189° C. CHN: Anal. Calcd. for C₂₆ H₂₃ Cl₂ N₃ O₃.0.45 H₂ O: C,62.91; H, 4.67; N, 8.47. Found: C, 61.89; H, 4.78; N, 8.33.

What is claimed is:
 1. A compound selected from the group consisting ofthe compounds depicted in the following Table:

    ______________________________________                                         ##STR208##                                                               

    ______________________________________                                         ##STR209##                                                                             R.sup.4           X         Y                                       ______________________________________                                        benzo     H                 O         O                                       benzo     H                 O         O                                       benzo     H                 O         O                                       benzo     H                 O         O                                       benzo     H                 O         O                                       benzo     H                 O         O                                       benzo     H                 O         O                                       benzo     H                 O         O                                        ##STR210##                                                                             H                 O         O                                        ##STR211##                                                                             H                 O         O                                       benzo                                                                                    ##STR212##       O         H.sub.2                                 benzo     H                 O         H.sub.2                                 benzo     H                 O         H.sub.2                                 benzo     H                                                                                                ##STR213##                                                                             O                                       benzo     H                                                                                                ##STR214##                                                                             O                                       ______________________________________                                                  ##STR215##                                                                             ZR.sup.1                                                   ______________________________________                                                 benzo                                                                                    ##STR216##                                                         benzo                                                                                    ##STR217##                                                         benzo                                                                                    ##STR218##                                                         benzo                                                                                    ##STR219##                                                         benzo                                                                                    ##STR220##                                                         benzo                                                                                    ##STR221##                                                         benzo                                                                                    ##STR222##                                                         benzo                                                                                    ##STR223##                                                         benzo                                                                                    ##STR224##                                                         benzo                                                                                    ##STR225##                                                         benzo                                                                                    ##STR226##                                                         benzo                                                                                    ##STR227##                                                         benzo                                                                                    ##STR228##                                                         benzo                                                                                    ##STR229##                                                         benzo                                                                                    ##STR230##                                                ______________________________________                                    


2. A pharmaceutical formulation comprising a pharmaceutically acceptablecarrier and an effective amount of the compound of claim
 1. 3. Acompound of structural formula: ##STR231## wherein Z is C₁₋₆ alkylene ora bond and R¹ is phenyl, phenyl substituted with --Cl, --Br, --I, --F,--CN or --CF₃, or R¹ is cyclohexyl.
 4. The compound of claim 3 whereinthe compound is selected from those depicted in the following Table:

    ______________________________________                                        Z                    R.sup.1                                                  ______________________________________                                        --(CH.sub.2).sub.2 --                                                                              2,4-diClPh                                               --(CH.sub.2).sub.2 --                                                                              4-ClPh                                                   --(CH.sub.2).sub.2 --                                                                              2,4-diFPh                                                --(CH.sub.2).sub.2 --                                                                              2-ClPh                                                   --(CH.sub.2).sub.2 --                                                                              4-CF.sub.3 Ph                                            --CH.sub.2 --        4-CF.sub.3 Ph                                            --(CH.sub.2).sub.2 --                                                                              3-CF.sub.3 Ph                                            --(CH.sub.2).sub.2 --                                                                              2-CF.sub.3 Ph                                            --(CH.sub.2).sub.2 --                                                                              cyclohexyl                                                 --                 cyclohexyl                                               --(CH.sub.2).sub.3 --                                                                              cyclohexyl                                               --CH.sub.2 --        cyclohexyl                                               --(CH.sub.2).sub.2 --                                                                              Ph                                                       --CH.sub.2 --        Ph                                                       --(CH.sub.2).sub.2 --                                                                              4-NCPh                                                   --(CH.sub.2).sub.2 --                                                                              3-ClPh                                                   --(CH.sub.2).sub.3 --                                                                              Ph                                                       --(CH.sub.2).sub.2 --                                                                              3-CNPh                                                   --(CH.sub.2).sub.2 --                                                                              2-thienyl                                                ______________________________________                                    


5. The compound of claim 4 of structural formula: ##STR232##
 6. Acompound of structural formula ##STR233## wherein Z is C₂₋₄ alkenyleneand R¹ is phenyl or phenyl substituted with --Cl, --Br, --F, --I, --CF₃,C₁₋₃ alkyl, C₁₋₃ alkoxy, nitro or methylenedioxy.
 7. The compound ofclaim 6, selected from those depicted in the following Table:

    ______________________________________                                        L          Z            R.sup.1                                               ______________________________________                                        735,801    CHCH         4-NO.sub.2 Ph                                         735,821    CHCH         2,4-diChPh                                            735,865    CHCH         3-ClPh                                                735,868    CHCH         2-ClPh                                                735,875    CHCH         2,4-diFPh                                             735,894    CHCH         2,6-diClPh                                            735,896    CHCH         4-CF.sub.3 Ph                                         738,048    CHCH         2-BrPh                                                738,052    CHCH         4-lPh                                                 738,067    CHCH         4-BrPh                                                366,333                                                                                   ##STR234##  Ph                                                    735,800    CHCH         3,4-diClPh                                            735,822    CHCH         4-CH.sub.3 Ph                                         735,826    CHCH         4-CH.sub.3 OPh                                        742,192    CHCH         3,4-methylenedioxyPh                                  738,049    CHCH         3-BrPh                                                ______________________________________                                    


8. The compound of claim 7 of structural formula: ##STR235##
 9. Thecompound of claim 7 of structural formula: ##STR236##
 10. A compound ofstructural formula: ##STR237## or a pharmaceutically acceptable saltthereof, wherein: R¹ is1) phenyl, either unsubstituted or substitutedwith one or two substituents selected froma) --NO₂, b) --Cl, --Br --F or--I, c) --CF₃, d) --C₁₋₃ alkyl, e) --C₁₋₃ alkoxy, f) --CN and g)-methylenedioxy, or 2) C₅₋₇ cycloalkyl; and R² is C₁₋₆ alkyl.
 11. Thecompound of claim 10 which is selected from the group consisting ofthose depicted in the following Table:

    ______________________________________                                               R.sup.1        R.sup.2                                                 ______________________________________                                               2,4-diClPh     --CH.sub.3                                                     2,4-diClPh     --C.sub.2 H.sub.5                                              2,4-diClPh                                                                    t-Bu                                                                          4-CF.sub.3 Ph  i-C.sub.3 H.sub.7                                              cyclohexyl     i-C.sub.3 H.sub.7                                              2,4-diClPh     i-C.sub.3 H.sub.7                                       ______________________________________                                    